ES2308018T3 - DERIVATIVES OF 6H-TIEN (2,3-B) PIRROL AS ANTAGONISTS OF THE GONADOTROPINE LIBERATING HORMONE (GNRH). - Google Patents

Abstract

A compound of formula (I), (See formula) in which: R 1 is selected from: hydrogen or unsubstituted C 1-6 alkyl; R 2 is an optionally substituted monocyclic aromatic ring, in which the optional substituents in R 2 are independently selected from: C1-6 alkyl, C2-6 alkenyl, cyano, nitro, C1-3 perfluoroalkyl, C1-3 perfluoroalkoxy, aryl, aryl-C1-6 alkyl, R 9 O (CH2) p-, R 9 C (O) O (CH2) w-, R 9 OC (O) (CH2) w-, R 16 S (On) ( CH2) w-, R 9 R 10 NC (O) (CH2) w-, R 9 R 10 N- or halogen; where w is an integer between 0 and 4, and R 9 and R 10 are as defined below; R 3 is selected from a group of Formula (IIa) to Formula (IIf): (See formulas) R 4 is selected from ...

Description

Derivatives 6H-tien [2,3-b] pyrrole as gonadotropin-releasing hormone antagonists (GnRH).

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The present invention relates to compounds which are antagonists of the activity of the releasing hormone of Gonadotropin (GnRH). The invention also relates to Pharmaceutical formulations, when using a compound of the present invention in the manufacture of a medicament, to a method of therapeutic treatment using said compound and to procedures to produce the compounds.

Gonadotropin-releasing hormone (GnRH) is a decapeptide that is secreted by the hypothalamus into the circulation pituitary portal in response to neural and / or chemical stimuli, producing the biosynthesis and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) by the pituitary. The GnRH is also known by other names, which include Gonadoliberin, LH releasing hormone (LHRH), releasing hormone of FSH (FSH RH) and LH / FSH release factor (LH / FSH RF).

GnRH has an important role in the regulation of the action of LH and FSH (by regulation of their levels), and therefore has a role in the regulation of gonadal steroid levels in both sexes, including Progesterone sex hormones, estrogens and androgens. Can be find more GnRH discussions in documents WO 98/5519 and WO 97/14697, whose descriptions are incorporated herein memory by reference.

It is believed that several diseases would benefit of the regulation of the activity of the GnRH, in particular by the antagonism of said activity. These include conditions related to sex hormones, such as cancer sex hormone dependent, benign prostatic hypertrophy and fibroids of the uterus Examples of hormone dependent cancers Sexual are prostate cancer, uterine cancer, breast cancer and gonadotrophic pituitary adenoma.

The following documents describe compounds which are intended to act as antagonists of GnRH: WO 97/21435, WO 97/21703, WO 97/21704, WO 97/21707, WO 55116, WO 98/55119, WO 98/55123, WO 98/55470, WO 98/55479, WO 99/21553, WO 99/21557, WO 99/41251, WO 99/41252, WO 00/04013, WO 00/69433, WO 99/51231, WO 99/51232, WO 99/51233, WO 99/51234, WO 99/51595, WO 99/51596, WO 00/53178, WO 00/53180, WO 00/53179, WO 00/53181, WO 00/53185, WO 00/53602, WO 02/066477, WO 02/066478, WO 02/06645 and WO 09/022565.

The following document describes compounds that It is intended to act as antagonists of GnRH: WO 02/24703.

It would be convenient to provide more compounds, said GnRH antagonist compounds being. Thus, according to the first aspect of the present invention a compound of Formula (I),

one

in the that:

R1

is selected from: hydrogen, alkyl C 1-6 optionally substituted, alkanoyl C 1-6 optionally substituted, aryl optionally substituted or aryl (C 1-6) alkyl optionally substituted;

R2

it is a mono or bicyclic aromatic ring optionally substituted;

R 3

is selected from a group of Formula (IIa) to Formula (IIf):

2

3

4

R 4

is selected from: hydrogen, alkyl C 1-6 optionally substituted, aryl optionally substituted, perfluoroalkyl C 1-3, cyano, nitro, halogen, R 9 O (CH 2) m -, R 9 C (O) N (R 10) (CH 2) m -, R 9 R 10 NC (O) N (R 10) (CH 2) m -, R 9 S (O n) (CH 2) m - or R 9 R 10 NC (O) - (CR 9 R 10) t (CH 2) m -,

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R 5

It is a group of formula (III):

5

R 6 and R 6a are selected regardless of hydrogen, fluorine, alkyl C 1-6 optionally substituted, aryl optionally substituted or aryl (C 1-6) alkyl optionally substituted, or R 6 and R 6a considered together and the carbon atom to which they are attached form a ring 3-7 member carbocyclic, or R 6 and R 6a considered together and the carbon atom to which they are attached form a carbonyl group; or when A is not a direct link, the group

6

quad

form a 3-7 carbocyclic ring carbon atoms or a heterocyclic ring containing one or more heteroatoms; or the group

7

quad

forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;

R 7

is selected from: hydrogen, alkyl C 1-6 optionally substituted, aryl (C 1-6) alkyl optionally substituted, aryl optionally substituted, optionally substituted heterocyclyl, heterocyclyl (C 1-6) alkyl  optionally substituted, R 9 O-(C 1-6) alkyl -, R 9 R 10 N-(C 1-6) alkyl -,

quad

R 9 R 10 NC (O) -alkyl (C 1-6), -C (NR 9 R 10) - NH;

or when R 3 is a group of formula (IIc) or (IId) R 7 can also be of formula

-J-K-R 8;

R 8

is selected from:

(i)

hydrogen, C 1-6 alkyl, C 2-6 alkenyl, alkynyl C 2-6, halogen-alkyl C_ {1-6}, (C 1-4) alkoxy-(C 1-4) alkyl,  hydroxy, hydroxyC 1-6 alkyl, cyano, N-(C 1-4) alkyl amino, N, N-di-(C 1-4) alkyl amino, (C 1-6) alkyl - S (O_n) -,  -O-R b, -NR b R c, -C (O) -R b, -C (O) O-R b, -CONR b R c, NH-C (O) -Rb or -S (O_n) NRbRc,

quad

in which R b and R c are selected independently of hydrogen and C 1-4 alkyl optionally substituted with hydroxy, amino, N-(C 1-4) alkyl amino,

quad

N, N-di-(C 1-4) alkyl amino, HO-(C 2-4) alkyl - NH- or HO-(C 2-4) alkyl - N (alkyl C 1-4) -;

(ii)

nitro when B is a group of formula (IV) and X is CH and p is 0;

(iii)

C 3-7 cycloalkyl, aryl or aryl (C 1-6) alkyl each one of which is optionally substituted with R 12, R 13 and R 14;

(iv)

- (Q) -aryl, - (Q) -heterocyclyl, -aryl- (Q) -aryl, each of which is optionally substituted with R 12, R 13 and R 14

quad

in which - (Q) - is selected of E, F or a direct link;

(v)

heterocyclyl or heterocyclyl (C 1-6) alkyl, each of which is optionally substituted with up to 4 substituents independently selected from R 12, R 13 and R 14;

(saw)

a group selected from R 12, R 13 and R 14;

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R 9 and R 10 are selected regardless of: hydrogen, hydroxy, alkyl C 1-6 optionally substituted, aryl optionally substituted, aryl (C 1-6) alkyl optionally substituted, an optionally carbocyclic ring 3-7 atom substituted, heterocyclyl optionally replaced, heterocyclyl (C 1-6) alkyl  optionally substituted, or R 9 and R 10 considered together they can form a ring of 3-9 atoms optionally substituted, or R 9 and R 10 taken together with the atoms of carbon to which they are attached form a group carbonyl;

R 11

is selected from: hydrogen, alkyl C 1-6 optionally substituted, or N (R 9 R 10);

R 12

is selected from: hydrogen, hydroxy, R 17 R 18 N (CH 2) cc -, R 17 R 18 NC (O) (CH 2) cc -, (C 1-6) alkyl - C (O) N (R 9) (CH 2) cc - optionally substituted, R 17 R 18 NC (O) N (R 9) (CH 2) cc -, R 17 R 18 NC (O) O (CH 2) cc -, (C 1-6) alkyl - OC (O) N (R 9) (CH 2) cc - optionally substituted, (C 1-6) alkyl - SO 2 N (R 9) - optionally substituted, aryl-SO 2 N (R 9) - optionally substituted, perfluoroalkyl (C 1-3) - SO 2 N (R 9) -; (C 1-6) alkyl - N (R 9) SO 2 - optionally substituted, aryl-N (R 9) SO 2 - optionally substituted, perfluoroalkyl (C 1-3) - N (R 9) SO 2 -, (C 1-6) alkanoyl - N (R 9) SO 2 - optionally substituted; aryl-C (O) N (R 9) SO 2 - optionally substituted, (C 1-6) alkyl - S (O_n) - optionally substituted, aril-S (O_ {n}) - optionally substituted, C 1-3 perfluoroalkyl, C 1-3 perfluoroalkoxy, alkoxy C 1-6 optionally substituted, carboxy, halogen, nitro or cyano;

R 13 and R 14 are selected Regardless of: hydrogen, hydroxy, oxo, alkyl C 1-6 optionally substituted, alkanoyl C 1-6 optionally substituted, alkenyl C 2-6 optionally substituted, cyano, nitro, C 1-3 perfluoroalkyl, perfluoroalkoxy C 1-3, optionally substituted aryl, aryl (C 1-6) alkyl optionally substituted, R 9 O (CH 2) s -, R 9 (O) O (CH 2) s -, R 9 OC (O) (CH 2) s -, R 16 S (O n (CH 2) s -, R 9 R 10 NC (O) (CH 2) s - or halogen;

R 15

is selected from: hydrogen, alkyl C 1-6 optionally substituted, R 19 OC (O) -, R 9 R 10 NC (O) -, R 9 C (O) -, R 9 S (O n) -;

R 16

is selected from: hydrogen, alkyl C 1-6, perfluoroalkyl C_ {1-3} or aryl optionally replaced;

R 17

is independently selected from: hydrogen, hydroxy, cyano or C 1-6 alkyl optionally replaced;

R 18

it's a formula group R 18a -C (R 9 R 10) 0-1 - wherein R 18a is selected from: R 19 OC (O) -, R 9 R 10 C (O) -, R 9 R 10 N-, R 9 C (O) -, R 9 C (O) N (R 10) -, R 9 R 10 NC (O) -, R 9 R 10 C (O) N (R 10) -, R 9 SO 2 N (R 10) -, R 9 R 10 NSO 2 N (R 10) -, R 9 C (O) O-, R 9 OC (O) -, R 9 R 10 NC (O) O-, R 9 O-, R 9 S (O n) -, R 9 R 10 NS (O n) -, hydrogen, C 1-6 alkyl optionally substituted, optionally substituted heterocyclyl; or

R 17 and R 18 when consider together they form a carbocyclic ring optionally substituted 3-7 atoms or heterocyclyl optionally replaced;

R 19

is selected from: hydrogen, alkyl C 1-6 optionally substituted, aryl optionally substituted, aryl (C 1-6) alkyl optionally substituted, C 3-7 cycloalkyl optionally substituted, optionally substituted heterocyclyl or heterocyclyl (C 1-6) alkyl optionally substituted;

R 20

is selected from R 12 or R 13;

R 21 and R 22 are selected independently of hydrogen, C 1-6 alkyl optionally substituted, C 3-7 cycloalkyl optionally substituted, optionally substituted heterocyclyl, heterocyclyl (C 1-6) alkyl  optionally substituted, C 3-6 alkenyl optionally substituted, C 3-6 alkynyl optionally substituted, - (alkyl C 1-5 (a) -S (O n) - (alkyl C 1-5) bb -; R 9 N 10 N-(C 2-6) alkyl,  R 9 O-(C 2-6) alkyl or R 9 R 10 NC (O) -alkyl (C 2-6), with the proviso that R 9 and R 10 independently or considered together they are not optionally substituted aryl or aryl (C 1-6) alkyl optionally substituted; or

R 21 and R 22 considered together they form a non-aromatic heterocyclic ring optionally replaced;

A is selected from:

(i)

a direct link;

(ii)

C 1-5 alkylene optionally substituted in which the optional substituents are independently selected from: alkyl C 1-6 optionally substituted, aryl optionally substituted or aryl (C 1-6) alkyl optionally substituted;

(iii)

a carbocyclic ring of 3-7 atoms;

(iv)

a carbonyl group or -C (O) -C (R d R d) -, wherein R d is independently selected from hydrogen and C 1-2 alkyl; or when R3 is a group of formula (IIa) or (IIb), the group

8

form a ring heterocyclic containing 3-7 carbon atoms and one or more heteroatoms; or when R 3 is a group of formula (IIa), (IIb), (IIc) or (IId), the group

9

form a ring heterocyclic containing 3-7 carbon atoms and one or more heteroatoms;

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B is selected from:

(i)

a direct link;

(ii)

a group of formula (IV)

in the that:

10

X is selected of N, CH or a saturated heterocyclic ring;

in which in the position (a) formula (IV) is attached to the nitrogen atom and the group (CH 2) p is attached to R 8; Y

(iii)

a group independently selected from: alkylene C 1-6 optionally substituted, cycloalkyl C 3-7 optionally substituted, alkenylene Optionally substituted C 3-6, alkynyl C 3-6 optionally substituted, alkoxy C 1-6, (alkyl C 1-5 (a) -S (O n) - (alkyl C_ 1-5) bb -, (alkyl C 1-5) aa -O- (alkyl C_ {1-5}) {bb} - or (rent C 1-5) aa -N (R 15) - (alkyl C_ 1-5) bb,

in which R 15 and the (alkyl) chain C 1-5) a (alkyl) C_ {1-5}) can be attached to form a ring;

or the group -B-R 8 represents a group of formula (V)

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eleven

or the group

12

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together it forms a heterocyclic ring optionally substituted containing 4-7 atoms of carbon; or the group

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13

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forms a heterocyclic ring that contains 3-7 carbon atoms and one or more heteroatoms;

E is -O-, -S (O_ {n}), -C (O) -, -NR 15 - or -C (R 9 R 10) q;

F is -E (CH 2) r - or - (CH 2) r E-;

G is selected from: hydrogen, halogen, CN, NO_ {2}, N, O, S (O_ {n}), C (O), C (R 9 R 10) t, alkenylene Optionally substituted C 2-6, alkynylene Optionally substituted C 2-6, heterocyclyl optionally substituted or a direct link to R18,

J is a group of formula: - (CH 2) s -L- (CH 2) s - in which when s is greater than 0, the alkylene group is optionally substituted, or the group

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14

together it forms a heterocyclic ring optionally substituted containing 4-7 atoms of carbon;

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K is selected from: a direct link, - (CH2) s1 -, - (CH2) s1 -O- (CH2) s2 -, - (CH2) s1 -C (O) - (CH2) s2 -, - (CH2) s1 -S (O_n) - (CH2) s2 -, - (CH2) s1 -N (R18) - (CH2) s2 -, - (CH 2) s 1 -C (O) N (R 9) - (CH 2) s 2 -, - (CH 2) s 1 -N (R 9) C (O) - (CH 2) s 2 -, - (CH 2) s 1 -N (R 9) C (O) N (R 9) - (CH 2) s 2 -, - (CH2) s1 -OC (O) - (CH2) s2 -, - (CH2) s1 -C (O) O- (CH2) s2 -, - (CH 2) s 1 -N (R 9) C (O) O- (CH 2) s 2 -, - (CH 2) s 1 -OC (O) N (R 9) - (CH 2) s 2 -, - (CH2) s1 -OS (O_n) - (CH2) s2 -,  or - (CH2) s1 -S (O_n) - O- (CH2) s2 -, - (CH 2) s 1 -S (O) 2 N (R 9) - (CH 2) s 2 -, - (CH 2) s 1 -N (R 9) S (O) 2 - (CH 2) s 2 -; in which the groups - (CH 2) s 1 - and - (CH2) s2 - are independently optionally substituted with hydroxy or alkyl C 1-4;

L is selected from aryl optionally substituted or optionally substituted heterocyclyl;

m is an integer from 0 to 4;

n is an integer from 0 to 2;

p is an integer from 0 to 4;

q is an integer from 0 to 4;

r is an integer from 0 to 4;

s is an integer from 0 to 4;

s1 and s2 are independently selected from a integer from 0 to 4, and s1 + s2 is less than or equal to 4; Y

t is an integer from 0 to 4;

aa and bb are independently selected from 0 or one;

cc is an integer from 0 to 2;

with the condition of

(i)

when G is hydrogen, halogen, CN or NO 2, then R 17 and R 18 are both missing;

(ii)

when G is O, S (O_ {n}), C (O) or C (R 11 R 12) t then G is substituted with a single independently selected group of the definition of R 17 or R 18, and when G is a bond direct to R 18 then G is substituted with a single group selected from R18; Y

(iii)

when R3 is a group of formula (IIb), B is a group of formula (TV), R 8 is selected of group (i) or (ii) above, R 11 is a group of formula N (R 10 R 11) and R 1, R 2 and R 5 are as defined above, then R 4 cannot be hydrogen;

or a salt, prodrug or solvate thereof.

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According to another feature of the first aspect of the invention, a compound of formula is provided (Ia),

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fifteen

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at that:

R1

is selected from hydrogen, alkyl C 1-6 optionally substituted, alkanoyl C 1-6 optionally substituted, aryl optionally substituted or aryl (C 1-6) alkyl optionally substituted;

R2

it is a mono or bicyclic aromatic ring optionally substituted;

R 3

is selected from a group of Formula (IIa) to Formula (IIf):

16

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17

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18

R 4

is selected from: hydrogen, alkyl C 1-6 optionally substituted, aryl optionally substituted, perfluoroalkyl C 1-3, cyano, nitro, halogen, R 9 O (CH 2) m -, R 9 C (O) N (R 10) -, R 9 R 10 NC (O) N (R 10) -, R 9 S (O n) - or R 9 R 10 NC (O) - (CR 9 R 10) t -;

R 5

It is a group of formula (III):

19

R 6 and R 6a are selected independently of hydrogen, C 1-6 alkyl optionally substituted, optionally substituted aryl or aryl (C 1-6) alkyl optionally substituted, or R 6 and R 6a considered together and the carbon atom to which they are attached form a ring 3-7 member carbocyclic, or R 6 and R 6a considered together and the carbon atom to which they are attached form a group carbonyl;

quad

or when A is not a direct link, the group

twenty

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quad

form a 3-7 carbocyclic ring carbon atoms or a heterocyclic ring containing one or more heteroatoms; or the group

twenty-one

quad

forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;

R 7

is selected from: hydrogen, alkyl C 1-6 optionally substituted, aryl (C 1-6) alkyl optionally substituted, aryl optionally substituted, optionally substituted heterocyclyl, heterocyclyl (C 1-6) alkyl  optionally substituted, R 9 O-(C 1-6) alkyl -, R 9 R 10 N-(C 1-6) alkyl -,

R 9 R 10 NC (O) -alkyl (C 1-6), -C (NR 9 R 10) = NH;

quad

or when R 3 is a group of formula (IIc) or (IId), R 7 is of formula -J-K-R 8;

R 8

is selected from:

(i)

hydrogen, C 1-6 alkyl, C 2-6 alkenyl, alkynyl C 2-6, halogen-alkyl C_ {1-6}, (C 1-4) alkoxy-(C 1-4) alkyl,  hydroxy, hydroxyC 1-6 alkyl, cyano, N-(C 1-4) alkyl amino, N, N-di-(C 1-4) alkyl amino, (C 1-6) alkyl - S (O_n) -,  -O-R b, -NR b R c, -C (O) -R b, -C (O) O-R b, -CONR b R c or NH-C (O) -Rb,

quad

in which R b and R c are selected independently of hydrogen and C 1-4 alkyl optionally substituted with hydroxy, amino, N-(C 1-4) alkyl amino,

quad

N, N-di-(C 1-4) alkyl amino, HO-(C 2-4) alkyl - NH- or HO-(C 2-4) alkyl - N (alkyl C 1-4) -;

(ii)

nitro when B is a group of formula (IV) and X is CH and p is 0;

(iii)

C 3-7 cycloalkyl, aryl or aryl (C 1-6) alkyl each one of which is optionally substituted with R 12, R 13 and R 14;

(iv)

- (Q) -aryl, - (Q) -heterocyclyl, -aryl- (Q) -aryl, each of which is optionally substituted with R 12, R 13 and R 14

quad

in which - (Q) - is selected of E, F or a direct link;

(v)

heterocyclyl or heterocyclyl (C 1-6) alkyl each of which is optionally substituted with R 12, R 13 and R 14;

(saw)

a group selected from R 12, R 13 and R 14;

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R 9 and R 10 are selected regardless of: hydrogen, hydroxy, alkyl C 1-6 optionally substituted, aryl optionally substituted, aryl (C 1-6) alkyl optionally substituted, an optionally carbocyclic ring 3-7 atom substituted, heterocyclyl optionally replaced, heterocyclyl (C 1-6) alkyl  optionally substituted, or R 9 and R 10 considered together they can form a ring of 3-9 atoms optionally substituted, or R 9 and R 10 considered together with the atoms of carbon to which they are attached form a group carbonyl;

R 11

is selected from: hydrogen, alkyl C 1-6 optionally substituted, or N (R 9 R 10);

R 12

is selected from: hydrogen, hydroxy, R 17 R 18 N-, (C 1-6) alkyl - SO 2 N (R 9) -  optionally substituted, aryl-SO 2 N (R 9) - optionally substituted,

quad

perfluoroalkyl (C 1-3) - SO 2 N (R 9) -; (C 1-6) alkyl - N (R 9) SO 2 - optionally substituted, aryl-N (R 9) SO 2 - optionally substituted, perfluoroalkyl (C 1-3) - N (R 9) SO 2 -, (C 1-6) alkanoyl - N (R 9) SO 2 -  optionally substituted; aryl-C (O) N (R 9) SO 2 - optionally substituted, (C 1-6) alkyl - S (O_n) -  optionally substituted, aril-S (O_ {n}) - optionally substituted, C 1-3 perfluoroalkyl, C 1-3 perfluoroalkoxy, alkoxy C 1-6 optionally substituted, carboxy, halogen, nitro or cyano;

R 13 and R 14 are selected independently of: hydrogen, C 1-6 alkyl optionally substituted, C 2-6 alkenyl optionally substituted, cyano, nitro, perfluoroalkyl C 1-3, perfluoroalkoxy C 1-3, optionally substituted aryl, aryl (C 1-6) alkyl optionally substituted, R 9 O (CH 2) s -, R 9 (O) O (CH 2) s -, R 9 OC (O) (CH 2) s -, R 16 (O n) (CH 2) s -, R 9 R 10 NC (O) (CH 2) s - or halogen;

R 15

is selected from: hydrogen, alkyl C 1-6 optionally substituted, R 19 OC (O) -, R 9 R 10 NC (O) -, R 9 C (O) -, R 9 S (O n) -;

R 16

is selected from: hydrogen, alkyl C 1-6, perfluoroalkyl C_ {1-3} or aryl optionally replaced;

R 17

is independently selected from: hydrogen, hydroxy, cyano or C 1-6 alkyl optionally replaced;

R 18

it's a formula group R 18a -C (R 9 R 10) 0-1 - wherein R 18a is selected from: R 19 OC (O) -, R 9 R 10 NC (O) -, R 9 R 10 N-, R 9 C (O) -, R 9 C (O) N (R 10) -, R 9 R 10 NC (O) -, R 9 R 10 NC (O) N (R 10) -, R 9 SO 2 N (R 10) -, R 9 R 10 NSO 2 N (R 10) -, R 9 C (O) O-, R 9 OC (O) -, R 9 R 10 NC (O) O-, R 9 O-, R 9 S (O n) -, R 9 R 10 NS (O n) -, optionally substituted C 1-6 alkyl, optionally substituted heterocyclyl; or

R 17 and R 18 when consider together they form a carbocyclic ring optionally substituted 3-7 atoms or heterocyclyl optionally replaced;

R 19

is selected from: hydrogen, alkyl C 1-6 optionally substituted, aryl optionally substituted, aryl (C 1-6) alkyl optionally substituted, C 3-7 cycloalkyl optionally substituted, optionally substituted heterocyclyl or heterocyclyl (C 1-6) alkyl optionally substituted;

R 20

is selected from R 12 or R 13;

R 21 and R 22 are selected independently of hydrogen, C 1-6 alkyl optionally substituted, C 3-7 cycloalkyl optionally substituted, optionally substituted heterocyclyl, heterocyclyl (C 1-6) alkyl  optionally substituted, C 3-6 alkenyl optionally substituted, C 3-6 alkynyl optionally substituted, - (alkyl C 1-5 (a) -S (O n) - (alkyl C 1-5) bb -; R 9 N 10 N-(C 2-6) alkyl,  R 9 O-(C 2-6) alkyl or R 9 R 10 NC (O) -alkyl (C 2-6), with the proviso that R 9 and R 10 independently or considered together they are not optionally substituted aryl or aryl (C 1-6) alkyl optionally substituted; or

R 21 and R 22 considered together they form a non-aromatic heterocyclic ring optionally replaced;

A is selected from:

(i)

a direct link;

(ii)

C 1-5 alkylene optionally substituted in which the optional substituents are independently selected from: alkyl C 1-6 optionally substituted, aryl optionally substituted, aryl (C 1-6) alkyl optionally substituted or aryl (C 1-6) alkyl replaced;

(iii)

a carbocyclic ring of 3-7 atoms;

(iv)

a carbonyl group;

or when R3 is a group of formula (IIa) or (IIb), the group

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22

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form a ring heterocyclic containing 3-7 carbon atoms and one or more heteroatoms; or when R 3 is a group of formula (IIa), (IIb), (IIc) or (IId), the group

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2. 3

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form a ring heterocyclic containing 3-7 carbon atoms and one or more heteroatoms;

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B is selected from:

(i)

a direct link;

(ii)

a group of formula (IV)

24

in the that:

X is selected of N, CH or a saturated heterocyclic ring;

in which in the position (a) formula (IV) is attached to the nitrogen atom and the group (CH 2) p is attached to R 8; Y

(iii)

a group independently selected from: alkylene C 1-6 optionally substituted, cycloalkyl C 3-7 optionally substituted, alkenylene Optionally substituted C 3-6, alkynyl C 3-6 optionally substituted, alkoxy C 1-6, (alkyl C 1-5 (a) -S (O n) - (alkyl C_ 1-5) bb -, (alkyl C 1-5) aa -O- (alkyl C_ {1-5}) {bb} - or (rent C 1-5) aa -N (R 15) - (alkyl C_ 1-5) bb,

in which R 15 and the (alkyl) chain C 1-5) a (alkyl) C_ {1-5}) can be attached to form a ring; or the group -B-R 8 represents a group of formula (V)

25

or the group

26

together it forms a heterocyclic ring containing 5-7 atoms of carbon; or the group

27

form a ring heterocyclic containing 3-7 carbon atoms and one or more heteroatoms;

E is -O-, -S (O_ {n}), -C (O) -, -NR 15 - or -C (R 9 R 10) q;

F is -E (CH 2) r - or - (CH 2) r E-;

G is selected from: hydrogen, halogen, CN, NO_ {2}, N, O, S (O_ {n}), C (O), C (R 9 R 10) t, alkenylene Optionally substituted C 2-6, alkynylene Optionally substituted C 2-6, heterocyclyl optionally substituted or a direct link to R18,

J is a group of formula: - (CH 2) s -L- (CH 2) s - in which when s is greater than 0, the alkylene group is optionally substituted,

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K is selected from: a direct link, -O- (CH2) s -, -C (O) - (CH2) s -, -S (O_n) - (CH 2) s -, -N (R 18) - (CH 2) s -, -OC (O) -
(CH2) s -, -C (O) O- (CH2) s -, -OS (O_n) - (CH2) s -, or -S (O_n) - O- (CH2) s -;

L is selected from aryl optionally substituted or optionally substituted heterocyclyl;

n is an integer between 0 and 2;

p is an integer between 0 and 4;

q is an integer between 0 and 4;

r is an integer between 0 and 4;

s is an integer between 0 and 4; Y

t is an integer between 0 and 4;

aa and bb are independently selected from 0 or one

with the condition of

(i)

when G is hydrogen, halogen, CN or NO 2, then R 17 and R 18 are both missing;

(ii)

when G is O, S (O_ {n}), C (O) or C (R 11 R 12) t then G is substituted with a single independently selected group of the definition of R 17 or R 18, and when G is a bond direct to R 18 then G is substituted with a single group selected from R18; Y

or a salt, prodrug or solvate thereof.

       \ vskip1.000000 \ baselineskip
    

According to another feature of the first aspect of the invention, a pharmaceutical formulation is provided  comprising a compound of formula (I) or formula (Ia), or one of its salts, prodrugs or solvates and a diluent or vehicle pharmaceutically acceptable.

According to another feature of the first aspect of the invention, the following uses of a compound of formula (I) or formula (Ia), or one of its salts, prodrugs or solvates:

(a) use in the manufacture of a medicine to antagonize the activity of the releasing hormone of Gonadotropin;

(b) use in the manufacture of a medicine to administer to a patient, to reduce the secretion of luteinizing hormone by the patient's pituitary gland; Y

(c) use in the manufacture of a medicine to administer to a patient, for therapeutic treatment and / or prevention of a condition related to sex hormones in the patient, preferably a hormone related condition sexually selected prostate cancer or breast cancer premenopausal

In accordance with another aspect of the invention, provides a method to antagonize the activity of the hormone Gonadotropin-releasing agent in a patient, comprising administering a compound of formula (I) or formula (Ia), or one of its salts, prodrugs or solvates, to a patient.

Although pharmaceutically preferred salts Acceptable of the compounds of the invention may also be other pharmaceutically acceptable salts of the invention are useful, for example in the preparation of pharmaceutically acceptable salts of the compounds of the invention.

Although the invention comprises compounds of the invention, and salts, prodrugs or solvates thereof, in other embodiment of the invention, the invention comprises compounds of the invention and salts thereof.

In the present specification, unless otherwise indicated, an alkyl, alkylene, alkenyl or alkynyl moiety may be linear or branched. The term " alkylene " refers to the group -CH2 -. Therefore, C 8 alkylene for example is - (CH 2) 8 -.

The term " propylene " refers to trimethylene and branched alkyl chains -CH (CH 3) CH 2 - and -CH 2 -CH (CH 3) -. Linear chain propylene dirradical is preferred, that is -CH2CH2CH2-. The specific propylene radicals refer to the particular structure, therefore the term propyl-2-ene refers to the group -CH2 -CH (CH3) -. A similar notation is used for other divalent alkyl chains such as butylene.

The term " 2-propenyl " refers to the group -CH2 -CH = CH-.

The term " aryl " refers to phenyl or naphthyl.

The term " carbamoyl " refers to the group -C (O) NH2.

The term " halogen " refers to fluorine, chlorine, bromine or iodine.

The term " heterocyclyl " or " heterocyclic ring " refers to a 4-12 membered aromatic mono or bicyclic ring, preferably 5-10 members, or a saturated or partially saturated mono or bicyclic ring, 4-12 members, preferably 5 -10 members, wherein said aromatic, saturated or partially unsaturated rings contain up to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, joined by ring carbon atoms or ring nitrogen atoms, in which a bond from a nitrogen, for example, a bond to the nitrogen of a pyridine ring is not possible, but a nitrogen bond 1 of a pyrazole ring is possible. Examples of 5 or 6 membered aromatic heterocyclic rings include pyrrolyl, furanyl, imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, isothiazolyl, thiazolyl and thienyl. A 9 or 10-membered bicyclic aromatic heterocyclic ring is an aromatic bicyclic ring system comprising a 6-membered ring fused to a 5-membered ring or another 6-membered ring. Examples of 5/6 and 6/6 bicyclic ring systems include benzofuranyl, benzimidazolyl, benzothiophenyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, indolyl, pyridoimidazolyl, pyrimidoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl and naphthyridinyl. Examples of saturated or partially saturated heterocyclic rings include pyrrolinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl and dihydropyrimidinyl. This definition also includes sulfur-containing rings in which the sulfur atom has been oxidized to an S (O) or S (O2) group.

The term " aromatic ring " refers to a 5-10 membered aromatic mono or bicyclic ring that optionally contains up to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur. Examples of such "aromatic rings" include: phenyl, pyrrolyl, furanyl, imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, isoxazolyl, oxazolyl, 1,2,4-oxadiazolyl, isothiazolyl, thiazolyl and thienyl. Preferred aromatic rings include phenyl, thienyl and pyridyl.

The symbol

28

indicates where the group is attached respective to the rest of the molecule.

For the avoidance of doubt, when two groups appear or integers in the same definition, for example, - (CH 2) s -L- (CH 2) s -  or R 9 R 10 NSO 2 N (R 10) -, then these They can be the same or different.

To avoid doubts, when several groups together they form a ring, for example: `` the group

29

forms a heterocyclic ring that contains 3-7 carbon atoms and one or more heteroatoms '', then the groups shown cycle to form a ring is tell

30

whose components are defined by the definitions of the groups that form the ring, so in the Previous example, the ring would include a nitrogen atom. By example, in example 2 this group forms a ring of piperazine

The term " C 1-3 perfluoroalkyl" refers to a C 1-3 alkyl chain in which all hydrogens have been replaced by fluorine atoms. Examples of C 1-3 perfluoroalkyl include trifluoromethyl, pentafluoroethyl and 1-trifluoromethyl-1,2,2,2-tetrafluoroethyl. Preferably, C 1-3 perfluoroalkyl is trifluromethyl.

Examples of C 1-8 alkyl include: methyl, ethyl, propyl, isopropyl, butyl, iso- butyl, tert-butyl and 2-methyl-pentyl; Examples of C 1-8 alkylene include: methylene, ethylene and 2-methyl propylene; examples of C 1-6 alkenyl include allyl (2-propenyl) and 2-butenyl, examples of C 1-6 alkynyl are 2-propyl and 3-butynyl, examples of halogen C 1-6 alkyl } include fluoroethyl, chloropropyl and bromobutyl, examples of C 1-6 hydroxyalkyl include hydroxymethyl, hydroxyethyl and hydroxybutyl, examples of C 1-8 alkoxy include methoxy, ethoxy and butyloxy; examples of (C 1-4) alkoxy-(C 1-4) alkyl include methoxyethyl, propoxybutyl and propoxymethyl, examples of C 1-6 alkanoyl include formyl, ethanoyl, propanoyl or pentanoyl, examples of N-C 1-4 alkyl amino include N -methylamino and N- ethylamino; examples of N, N-di-(C 1-4) alkyl amino include N, N-dimethylaminoethyl, N, N-di-methylaminopropyl and N, N-dipropylaminoethyl, examples of HO-alkyl (C 2 -4}) - NH include hydroxymethylamino hydroxyethylamino and hydroxypropylamino, examples of HO-(C 2-4) alkyl-N (C 1-4 alkyl) include N-methyl-hydroxymethylamino, N-ethyl-hydroxyethylamino, and N-propyl-hydroxypropylamino, examples of (C 1-6) alkyl-S (O n) - include methylthio, methylsulfinyl, ethylsulfinyl, ethylsulphonyl and propylsulfonyl, examples of aryl (C 1-8 alkyl) 6}) include benzyl, phenethyl and phenylbutyl, examples of heterocyclyl (C 1-6) alkyl include pyrrolidin-1-yl-ethyl, imidazolylethyl, pyridylmethyl and
pyrimidinylethyl.

You have to understand that, to the extent that some of the compounds of the invention may exist in forms optically active or racemic by virtue of one or more atoms of asymmetric carbon, the invention includes in its definition any of said optically active or racemic forms that have the property of antagonizing the activity of the hormone Gonadotropin-releasing (GnRH). The synthesis of forms optically active can be carried out by techniques organic chemistry standard well known in the art, by example by synthesis from optically starting materials assets or by resolution in a racemic way. Also, the activity of those compounds can be evaluated using the techniques laboratory standard cited below.

This invention also relates to any and all tautomeric forms of the compounds of the different characteristics of the invention, which have the property of antagonize gonadotropin releasing hormone activity (GnRH).

It should also be understood that certain compounds of the present invention may exist in forms solvatates, for example, hydrated, as well as without solvating. Must understand that the present invention encompasses all such forms solvatates that have the property of antagonizing the activity of the Gonadotropin-releasing hormone (GnRH).

Preferred compounds of formula (I) are those in which any and any combination of the following.

Preferably R 1 is selected from hydrogen or optionally substituted C 1-6 alkyl. More preferably, R 1 represents hydrogen or unsubstituted C 1-6 alkyl. Even more preferably, R 1 represents hydrogen, methyl, ethyl or tert-butyl . Most preferably, R 1 represents hydrogen.

Preferably, the optional substituents in R1 are independently selected from: alkyl C 1-6 optionally substituted, alkenyl C 2-6 optionally substituted, cyano, nitro, C 1-3 perfluoroalkyl, perfluoroalkoxy C 1-3, optionally substituted aryl, aryl (C 1-6) alkyl optionally substituted, R 9 O (CH 2) v -; R 9 C (O) O (CH 2) v -, R 9 OC (O) (CH 2) v -, R 16 S (O n) (CH 2) v -, R 9 R 10 NC (O) (CH 2) v -, or halogen in which v is an integer between 0 and 4, and when present 2 optional substituents together, can optionally form a C 3-7 carbocyclic ring or a ring heterocyclic

Preferably, R2 is a structure optionally substituted monocyclic aromatic ring. The most preferably, R2 represents phenyl optionally replaced.

Preferably, the optional substituents on R 2 are independently selected from: optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, cyano, nitro, C 1-3 perfluoroalkyl, C_ perfluoroalkoxy {1-3}, optionally substituted aryl, optionally substituted aryl (C 1-6) alkyl, R 9 O (CH 2) p -, R 9 C (O ) O (CH 2) w -, R 9 OC (O) (CH 2) w -, R 16 S (O n) (CH_ { 2) w -, R 9 R 10 NC (O) (CH 2) w -, R 9 R 10 N- or halogen; where w is an integer between 0 and 4, and R 9 and R 10 are as defined above. In addition, preferably the optional substituents at R2 are independently selected from cyano, R e R f N-, optionally substituted C 1-6 alkyl (preferably, C 1-4 alkyl , e.g., methyl or ethyl), optionally substituted C 1-6 alkoxy (preferably, C 1-4 alkoxy, e.g., methoxy, ethoxy or tert- butoxy) or halogen (e.g. ., F, Br or Cl) in which R e and R f are independently selected from hydrogen, C 1-6 alkyl or aryl. Even more preferably, the optional substituents on R2 are independently selected from methyl, ethyl, methoxy, ethoxy, tert- butoxy, F or Cl. Most preferably, the optional substituents on R2 are independently selected from methyl, F or Cl. Preferably, R2 carries 1, 2 or 3 substituents.

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Most preferably, R2 represents

31

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Preferably, R 3 is selected from the group of formula (IIa), formula (IIb), formula (IIc) or formula (IId). The more preferably, R 3 is a group of formula (IIc) or formula (IId).

Preferably, R 4 is selected from hydrogen or C 1-4 alkyl. The most preferably, R 4 is hydrogen. Preferably, the group of formula (III):

32

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is selected from one of a group of formula III-a a III-1;

33

3. 4

35

in the that:

het

represents a heterocyclic ring from 3 to 8 members, optionally substituted, containing 1 to 4 heteroatoms independently selected from O, N and S;

quad

R 23 and R 23a are selected Independently of:

(i)

hydrogen, fluorine or C 1-8 alkyl optionally substituted; or

(ii)

R 23 and R 23a together with the carbon to which they are joined form a 3 to 7 membered cycloalkyl ring optionally substituted;

quad

R 24 and R 25 are selected from:

(i)

R 24 selected from hydrogen; I rent C 1-8 optionally substituted; aryl optionally substituted; -R d -Ar, in which R d represents C 1-8 alkylene and Ar represents optionally substituted aryl; and heterocyclic ring 3 to 8 optionally substituted members containing 1 to 3 additional heteroatoms independently selected from O, N and S; and R25 is selected from hydrogen; I rent Optionally substituted C 1-8 and aryl optionally substituted;

(ii)

when the group of formula (III) represents a group of formula III-a, III-b or III-i, then the NR 24 (- R 25) group represents a 3- to 8-membered heterocyclic ring optionally substituted optionally containing 1 to 3 heteroatoms additional independently selected from O, N and S; or

(iii)

when the group of formula (III) represents the structure III-e,

36

quad

represents a heterocyclic ring from 3 to 8 members, optionally substituted, which optionally contains 1 to 4 heteroatoms independently selected from O, N and S; R 26 is selected from hydrogen or alkyl C_ {1-4}. Preferably, R 26 is selected of hydrogen, methyl or ethyl. Most preferably, R 26 is hydrogen.

Preferably, the group of formula (III) is select from a group of formula III-a, III-g, III-h or III-i:

37

       \ vskip1.000000 \ baselineskip
    

38

in which R 23, R 23a, R 24 and R 25 are as defined previously.

In addition, preferably the group of formula (III) is selected from one of the following groups:

39

in which R 23, R 23a, R 24 and R 25 are as defined previously.

Even more preferably the group of formula (III) is selected from one of the following groups:

40

41

in which he represents me methyl.

Even more preferably the group of formula (III) is selected from one of the following groups:

42

Most preferably, the group of formula (III) is:

43

Preferably, R 6 and R 6a are independently select hydrogen, fluorine or alkyl C 1-6 optionally substituted. Preferably, R 6 and R 6a are selected independently of hydrogen and C 1-6 alkyl not replaced Even more preferably, R 6 and R 6a are independently selected from hydrogen or methyl. The most preferably, R 6 and R 6a are both hydrogen.

Preferably, R 7 is selected from: hydrogen or C 1-4 alkyl. More preferably, R 7 is hydrogen or methyl. Most preferably, R 7 is hydrogen.

When R 8 is heterocyclyl then R 8 It is preferably selected from one of the following groups:

44

440

in which Z is selected from: O, S or N (R 9), R 20 is selected from any group within the definitions of R 12 and R 13, and R 9, R 12, R 13 and R 14 are as defined previously.

In another embodiment of the invention, when R 8 is heterocyclyl then R 8 is selected preferably from one of the following groups:

Four. Five

450

46

in which Z is selected from: O, S or N (R 9) and R 9, R 12 and R 13 are as they have been definite previously.

When R 8 is aryl or aryl- (Q) -aryl optionally substituted with R 12, R 13 and R 14, R 8 is selected preferably from one of the following groups:

47

in which D is selected from group E, group F or a link direct;

Preferably, R 8 is selected from:

(i)

hydrogen, alkyl C 1-6, C 2-6 alkenyl, halogen-C 1-6 alkyl, hydroxy, cyano, (C 1-6) alkyl - S (O_n) -,  -O-R b, (C 1-4) alkoxy-(C 1-4) alkyl, -C (O) -R b, C (O) O-R b, -NH-C (O) -R b, N, N-di-(C 1-4) alkyl amino, -S (O_n) NR b R c

in which R b and R c are independently selected from hydrogen and C 1-6 alkyl, and n is 0, 1 or 2;

(ii)

- (Q) -aryl, wherein the aryl is optionally substituted;

(iii)

heterocyclyl C4-7 optionally substituted,

plus preferably C 4-7 heterocyclyl optionally substituted selected from: azirinyl, azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, hexahydropyridazinyl, hexahydrotriazinyl, tetrahydrotriazinyl, dihydrotriazinyl, tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl, dioxanyl, trioxanyl, tetrahydrothienyl, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothienyl, tetrahydrothiopyran, 1-oxotetrahydrothiopyran, 1,1-dioxotetrahydrothiopyran, dithianyl, trityanyl, morpholinyl, oxathiolanyl, oxathianyl, thiomorpholinyl, thiazinanyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, thiazolidinyl, pyrrolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, thiazolyl, thiadiazolyl, thiadiazinyl, oxazolyl, isoxazolyl, oxadiazolyl, furazanyl, octahydropyrrolopyrrolyl, octahydropyrrolopyrrolyl, benzotriazolyl, dihydrobenzotriazolyl, indolyl, indolinyl, benzimidazolyl, 2,3-dihydrobenzimidazolyl, benzotriazolyl, 2,3-dihydro-benzotriazolyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinozalinyl, naphthyridinyl, pteridinyl, benzodioxolyl, tetrahydrodioxolopyrrolyl, 1,5-dioxa-9-azaespiro [5.5] undecanyl Y 8-oxa-3-azabicyclooctanyl; or

(iv)

carbocyclyl C 3-7 optionally substituted;

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More preferably, R 8 is selected from:

(i)

hydrogen, alkyl C 1-6, C 2-6 alkenyl, halogen-C 1-6 alkyl, hydroxy, cyano, (C 1-6) alkyl - S (O_n) -,  -O-R b, (C 1-4) alkoxy-(C 1-4) alkyl, -C (O) -R b, C (O) O-R b, -NH-C (O) -R b,

N, N-di-(C 1-4) alkyl amino, -S (O_n) NR b R c

in which R b and R c are independently selected from hydrogen and C 1-6 alkyl, and n is 0, 1 or 2;

(ii)

- (Q) -aryl, wherein the aryl is optionally substituted;

(iii)

heterocyclyl Optionally substituted C_ {4-7} selected from: azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, morpholinyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, imidazolyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl, tetrahydro-3aH- [1,3] dioxolo [4,5-c] pyrrolyl, 1,5-dioxa-9-azaespiro [5.5] undecanyl, 8-oxa-3-azabicyclo [3.2.1] octanyl,  benzodioxolyl, 2,3-dihydrobenzotriazolyl and octahydropyrrolo [3,4-c] pyrrolyl; or

(iv)

carbocyclyl C 3-7 optionally substituted;

       \ vskip1.000000 \ baselineskip
    

Even more preferably, R 8 is select from:

(i)

hydrogen, methyl, isopropyl, t -butyl, 1-methylethyl, allyl, fluoroethyl, hydroxy, cyano, ethylsulfonyl, methoxy, 1-methyl-2-methoxyethyl, acetyl, t-butoxycarbonyl, acetylamino, dimethylamino, diethylamino, (1-methyl ethyl ) amino, isopropylamino or aminosulfonyl;

(ii)

phenyl optionally replaced;

(iii)

heterocyclyl Optionally substituted C_ {4-7} selected from: azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, morpholinyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, imidazolyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl, tetrahydro-3aH- [1,3] dioxolo [4,5-c] pyrrolyl, 1,5-dioxa-9-azaespiro [5.5] undecanyl, 8-oxa-3-azabicyclo [3.2.1] octanyl, benzodioxolyl, 2,3-dihydrobenzotriazolyl or octahydropyrrolo [3,4-c] pyrrolyl; or

(iv)

carbocyclyl Optionally substituted C_ {3-7} selected from: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

       \ vskip1.000000 \ baselineskip
    

Even more preferably, R 8 is select from C4-7 heterocyclyl optionally substituted selected from: piperidinyl or piperazinyl, azetidinyl, imidazolyl and thiazolyl.

Most preferably, R 8 is heterocyclyl Optionally substituted C_ {4-7} selected from: piperidinyl or piperazinyl.

In another embodiment of the invention R 8 is select from hydrogen, cyano, C 1-4 alkyl (more preferably methyl), C 2-6 alkynyl (more preferably 2-propynyl), hydroxyC 1-6 alkyl (more preferably hydroxyethyl), (C 1-4) alkoxy - (C 1-4) alkyl (more preferably methoxyethyl), halogen-alkyl C 1-6 (more preferably fluoroethyl), C 1-4 alkanoyl (more preferably formyl), (C 1-4) alkoxycarbonyl (more preferably butyloxycarbonyl), N, N-di-(C 1-4) alkyl amino (more preferably N, N-dimethylaminoethyl and N, N-dimethylaminopropyl), (C 1-6) alkyl - S (O_n) - (more preferably ethylsulfonyl), cyclopentyl, phenyl, benzyl, cyanophenyl, pyrrolidinyl, pyrrolidinylethyl, imidazolyl, imidazolyl (C 1-6) alkyl  (more preferably imidazolylethyl), thiazolyl, pyridyl, pyridyl (C 1-6) alkyl (more preferably pyridylmethyl) or pyrimidyl in which the phenyl or heterocyclyl ring is optionally substituted with C 1-4 alkyl.

When R 9 and / or R 10 is a component of the group G, R 9 and R 10 are preferably selected so hydrogen independent, C 1-6 alkyl optionally substituted, aryl optionally substituted, aryl (C 1-6) alkyl optionally substituted or R 9 and R 10 form cycloalkyl C 3-7 or heterocyclyl. More preferably hydrogen or C 1-4 alkyl. The most preferably hydrogen or methyl. Most preferably so much R 9 as R 10 are methyl.

When R 9 and / or R 10 is a component of the group G, R 18, R 9 and R 10 are preferably selected  independently of hydrogen, alkyl C 1-6 optionally substituted, aryl optionally substituted, aryl (C 1-6) alkyl optionally substituted, or R 9 and R 10 form cycloalkyl C 3-7 or heterocyclyl. More preferably when R 9 is a component of the group R 18, R 9 is preferably heterocyclyl. Most preferably pyrrolidinyl, 7-azabicyclo [2.2.1] hept-7-yl or 3-azabicyclo [3.2.2] nonyl.

Preferably, R17 is hydrogen, hydroxy, cyano or absent Most preferably, R 17 is absent.

Preferably, R18 is selected from hydrogen, R 9 N (R 10) C (O) -, R 9 C (O) -, R 9 OC (O) - or R 18a -C (R 9 R 10) - en which R 18a is R 9 N (R 10) C (O) -. More preferably R 9 C (O) -. Most preferably R 9 C (O) - in which R 9 is heterocyclyl.

Preferably, A is selected from a link direct, C 1-5 alkylene optionally substituted, carbonyl or -C (O) -C (R d R d) -, wherein R d is independently selected from hydrogen and C 1-2 alkyl. More preferably A is a direct bond, C 1-5 alkylene optionally substituted with C 1-4 alkyl, carbonyl or carbonylmethyl Even more preferably A is a direct link, unsubstituted C 1-2 alkylene or carbonyl. The more preferably A is methylene.

Preferably, B is selected from alkylene Optionally substituted C_ {1-6} or group

48

form a heterocyclic ring C_ {4-7} optionally replaced.

More preferably, B is alkylene. C_ {1-6} or the group

49

form a heterocyclic ring C_ {4-7} optionally saturated replaced.

More preferably, B is alkylene. C_ {1-6} unsubstituted or group

fifty

form a heterocyclic ring Optionally substituted saturated C 4-7 selected from: azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, hexahydropyridazinyl, hexahydrotriazinyl, tetrahydrotriazinyl, dihydrotriazinyl, morpholinyl, thiomorpholinyl, thiazinanyl, thiazolidinyl, 1,5-dioxa-9-azaespiro [5.5] undecanyl or octahydropyrrolopyrrolyl, in which the substituents Optional are selected from cyano, hydroxy, oxo, alkyl C 1-4, C 1-4 alkoxy, C 1-4 alkanoyl, R 9 OC (O) (CH 2) w -, R 9 R 10 NC (O) (CH 2) w - or halogen, in which w is an integer between 0 and 4, and R 9 and R 10 are as defined above. More preferably  Optional substituents are selected from: cyano, hydroxy, oxo, C 1-4 alkyl, alkoxy C 1-4 and alkanoyl C_ {1-4}.

Even more preferably, B is selected from: ethylene, propylene or butylene or the group

51

form a heterocyclic ring Optionally substituted saturated C 4-7 selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,5-dioxa-9-azaespiro [5.5] undecanyl or octahydropyrrolopyrrolyl, in which the substituents optional are selected from oxo.

       \ vskip1.000000 \ baselineskip
    

Most preferably the group

52

form a heterocyclic ring Optionally substituted saturated C 4-7 selected from: piperidinyl or piperazinyl, in which the optional substituents are selected from oxo.

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In another embodiment of the invention B select from C 1-6 alkylene optionally substituted or group

53

form a heterocyclic ring C_ {5-7}. Preferably alkylene C 1-6 unsubstituted or a heterocyclic ring C_ {5-7} saturated. Most preferably methylene, ethylene, propylene, butylene or piperazinyl

       \ vskip1.000000 \ baselineskip
    

Preferably, G is a direct link, -O- or -C (R 9 R 10) -. Plus preferably -C (R 9 R 10) -. The most preferably -C (CH 3) 2 -.

       \ vskip1.000000 \ baselineskip
    

When R 3 is selected from a group of formula (IIe) or formula (IId) then the group

54

preferably form a ring optionally substituted heterocyclic containing 4-7 atoms of carbon.

       \ vskip1.000000 \ baselineskip
    

More preferably the group

55

form a heterocyclic ring C_ {4-7} optionally saturated replaced.

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More preferably the group

56

form a heterocyclic ring Optionally substituted saturated C 4-7 selected from: azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, hexahydropyridazinyl, hexahydrotriazinyl, tetrahydrotriazinyl, dihydrotriazinyl, morpholinyl, thiomorpholinyl, thiazinanyl, thiazolidinyl or octahydropyrrolopyrrolyl, in which the optional substituents are selected from oxo.

More preferably the group

57

form a heterocyclic ring Optionally substituted saturated C 4-7 selected from: pyrrolidinyl, piperidinyl or piperazinyl, in the that optional substituents are selected from oxo.

Most preferably the group

58

form a heterocyclic ring Optionally substituted saturated C 4-7 selected from: piperidinyl or piperazinyl, in which the optional substituents are selected from oxo.

Preferably K is selected from: - (CH 2) s -, - (CH 2) s -O- (CH 2) s -, - (CH 2 ) s -C (O) - (CH 2) s -, - (CH 2) s -N (R 18) -
(CH 2) s -, - (CH 2) s -C (O) N (R 18) - (CH 2) s -, - (CH 2) s -N (R 18) C (O) - (CH 2) s -, - (CH 2) s -S ( O) 2 N (R 18) - (CH 2) s -, or - (CH 2) s -NHS
(O) 2 - (CH 2) s -, in which s is independently selected from 0, 1, 2, 3 or 4, R 18 is selected from hydrogen or C_ alkyl {1-4 (preferably hydrogen) and the group - (CH2) s - is optionally substituted with hydroxy or C1-4 alkyl.

More preferably K is selected from: - (CH 2) s 1 -, - (CH 2) s 1 -O- (CH 2) s 2 -, - (CH_ { 2) s1 -C (O) -, -C (O) - (CH2) s2 -,
- (CH2) s1 -N (R18) -, - (CH2) s1 -C (O) N (R18) -, - ( CH2) s1 -N (R18) C (O) - (CH2) s2 -, - (CH2) s1 -S (O ) 2 N (R 18) - or - (CH 2) s1 -NHS
(O) 2 -,

in which s1 and s2 are selected regardless of 0, 1, 2, 3 or 4 and s1 + s2 is less than or equal to 4, R 18 is selected from hydrogen or alkyl C 1-4 (preferably hydrogen) and the group - (CH 2) s - is optionally substituted with hydroxy or C 1-4 alkyl.

More preferably K is selected from: methylene, ethylene, propylene, oxy, 2-hydroxypropylene, carbonyl, methylcarbonyl, ethylcarbonyl, (methyl) methylcarbonyl, (ethyl) methylcarbonyl, carbonylmethylene, carbonylethylene, ethoxyethylene, amino, 2-hydroxypropylamino, carbonylamino, methylcarbonylamino, aminocarbonyl, methylaminocarbonyl, methylaminocarbonylmethyl, propylsulfonylamino or methylaminosulfonyl.

More preferably K is selected from: methylene, carbonyl, carbonylamino, methylcarbonylamino, aminocarbonyl, methylaminocarbonyl or methylaminosulfonyl.

Most preferably K is selected from: methylene, carbonyl or methylcarbonylamino;

Preferably, the optional substituents in heterocyclyl groups in R 8, R 9, R 10, R 18 and R 19 or in heterocyclyl groups formed when R 17 and R 18 together form a heterocyclic ring, are selected from: optionally substituted C 1-6 alkyl, alkoxy C 1-6, C 1-6 alkanoyl, optionally substituted C 2-6 alkenyl, cyano, nitro, C 1-3 perfluoroalkyl, C 1-3 perfluoroalkoxy, aryl optionally replaced, aryl (C 1-6) alkyl optionally substituted, R 9 O (CH 2) p -, R 9 C (O) O (CH 2) w -, R 9 OC (O) (CH 2) w -, R 16 S (O n) (CH 2) w -, R 9 R 10 NC (O) (CH 2) w - or halogen; where w is an integer between 0 and 4 and p, R 9, R 10 and R 16 are as defined above.

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More preferably the optional substituents in R 8 they are selected from: cyano, hydroxy, oxo, alkyl C 1-4, C 1-4 alkoxy, C 1-4 alkanoyl, R 9 OC (O) (CH 2) w -, R 9 R 10 NC (O) (CH 2) w - or halogen, in which w is an integer between 0 and 4, and R 9 and R 10 are as defined above.

More preferably the optional substituents in R 8 they are selected from: cyano, hydroxy, oxo, alkyl C 1-4, C 1-4 alkoxy and C 1-4 alkanoyl.

Most preferably substituents Optional in R 8 are selected from: cyano, oxo, methyl, methoxy and acetyl.

Preferably, the optional substituents in alkyl, alkenyl, alkunyl, cycloalkyl and aryl groups are independently selected from C 1-6 alkyl, C 1-6 alkoxy, cycloalkyl C 3-7, optionally substituted aryl, aryl (C 1-6) alkyl optionally substituted, hydroxy, oxo, cyano, alkoxy C 1-6, halogen (preferably fluorine), R 16 S (O n) (CH 2) w -, R 9 OC (O) -, aryl-alkoxy (C 1-3) optionally substituted in which R 9 is as defined previously.

Preferably the optional substituents in the aryl groups and aryl (C 1-6) alkyl optionally substituted are selected from: alkyl C 1-6 optionally substituted, alkenyl C 2-6 optionally substituted, cyano, nitro, halogen (preferably fluorine), perfluoroalkyl C 1-3, perfluoroalkoxy C 1-3, optionally substituted aryl, aryl (C 1-6) alkyl optionally substituted, R 9 O (CH 2) p -, R 9 C (O) O (CH 2) w -, R 9 OC (O) (CH 2) w -, R 16 S (O n) (CH 2) w -, R 9 R 10 NC (O) (CH 2) w - or halogen; where w is an integer between 0 and 4, and n, R 9 and R 10 are as defined above.

In the preferences for heterocyclyl in R 8 nitrogen atoms in heteroaromatic rings R 8 exist as represented, or when chemically allowed, in its oxidized state (N \ rightarrowO, N-OH).

When the optional substitution at different sites is mentioned, the optional substituents also comprise the following definition that refers to one, two, three or more optional substituents. Unless otherwise indicated above (that is, when a list of optional substituents is specifically given in a definition), each substituent can be independently selected from C 1-8 alkyl (eg, C 2- alkyl) 6}, and most preferably methyl, ethyl or tert-butyl ); C 3-8 cycloalkoxy, preferably cyclopropoxy, cyclobutoxy or cyclopentoxy; C 1-6 alkoxy, preferably methoxy or C 2-4 alkoxy; halogen, preferably Cl or F; Hal 3 C-, Hal 2 CH-, HalCH 2 -, Hal 3 CO-, Hal 2 CHO or Hal CH 2 O, in which Hal represents halogen (preferably F) ; R g CH 2 O-, R h C (O) N (R) -, R h SO 2 N (R) - or R g -R ^ {h} N-, in which R g and R h independently represent hydrogen or C 1-8 alkyl (preferably methyl or C 2-6 alkyl or C 2-4 alkyl ), or R g -R h N- represents a C 3-8 heterocyclic ring, preferably optionally substituted C 3-6, which optionally contains 1 to 3 additional heteroatoms independently selected from O , N and S; hydrogen; or R k C (O) O- or R k C (O) -, R k representing hydrogen, optionally substituted phenyl or C 1-6 alkyl (preferably methyl, ethyl, iso -propyl or tert -butyl). For the optional substitution of the heterocyclic ring represented by R g -R b N-, at least one (eg, one, two or three) substituent can be provided independently selected from C 1-1 alkyl 6} (eg, C 2-4 alkyl, more preferably methyl); phenyl; CF 3 O-; F 2 CHO-; C 1-8 alkoxy, preferably methoxy, ethoxy or C 3-6 alkoxy; (C 1-8) alkoxy-C (O), preferably methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl or (C 3-6) alkoxy-C (O) -; phenoxycarbonyl; phenoxy; C 1-8 alkanoyl, preferably acetyl, ethanoyl or C 3-6 alkanoyl; carboxy; (C 1-8) alkyl-S (O_nn) in which nn is an integer between 0 and 2, preferably methylthio, ethylthio, C 3-6 alkylthio, methylsulfinyl, ethylsulfinyl, C_alkylsulfinyl 3-6, methylsulfonyl, ethylsulfonyl or C 3-6 alkylsulfonyl; hydroxy; halogen (e.g., F, Cl or Br); R m R n N- wherein R m and R n are independently hydrogen or C 1-6 alkyl (preferably C 2-4 alkyl, more preferably methyl , most preferably R m = R n = methyl); and nitro.

According to another aspect of the present invention, provides a compound of formula (Ib)

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59

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in the that:

R1 represents hydrogen or alkyl C 1-6 unsubstituted;

R2 represents phenyl optionally replaced;

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R 3 is selected from a group of Formula (IIa) to Formula (IId):

60

61

R 4 is selected from hydrogen or alkyl C 1-4;

R 5 is selected from one of a group of formula III-a to III-j:

62

63

64

in the that:

het

represents a heterocyclic ring from 3 to 8 members, optionally substituted, containing 1 to 4 heteroatoms independently selected from O, N and S;

quad

R 23 and R 23a are selected Independently of:

(i)

hydrogen, fluorine or C 1-8 alkyl optionally substituted; or

(ii)

R 23 and R 23a together with the carbon to which they are joined form a 3 to 7 membered cycloalkyl ring optionally substituted;

quad

R 24 and R 25 are selected from:

(i)

R 24 selected from hydrogen; I rent C 1-8 optionally substituted; aryl optionally substituted; -R d -Ar, in which R d represents C 1-8 alkylene and Ar represents optionally substituted aryl; and heterocyclic ring 3 to 8 optionally substituted members containing 1 to 3 additional heteroatoms independently selected from O, N and S; and R25 is selected from hydrogen; I rent Optionally substituted C 1-8 and aryl optionally substituted;

(ii)

when the group of formula (III) represents a group of formula III-a, III-b or III-i, then the NR 24 (- R 25) group represents a 3- to 8-membered heterocyclic ring optionally substituted optionally containing 1 to 3 heteroatoms additional independently selected from O, N and S; or

(iii)

when the group of formula (III) represents the structure III-e,

65

quad

represents a heterocyclic ring from 3 to 8 members, optionally substituted, which optionally contains 1 to 4 heteroatoms independently selected from O, N and S;

quad

R 26 is selected from hydrogen or alkyl C_ {1-4}.

R 6 and R 6a are selected regardless of hydrogen, fluorine or alkyl C_ {1-6} optionally replaced.

R 7

is selected from: hydrogen or alkyl C 1-4;

R 8

is selected from:

(i)

hydrogen, C 1-6 alkyl, C 2-6 alkenyl, halogen-C 1-6 alkyl, hydroxy, cyano, (C 1-6) alkyl - S (O_n) -,  -O-R b, (C 1-4) alkoxy-(C 1-4) alkyl, -C (O) -R b, C (O) O-R b, -NH-C (O) -R b, N, N-di-(C 1-4) alkyl amino or -S (O_n) NR b R c

quad

in which R b and R c are selected independently of hydrogen and C 1-6 alkyl, and n is 0, 1 or 2;

(ii)

-aryl, optionally substituted with up to 4 substituents selected from R 12, R 13 and R 14;

(iii)

C 4-7 heterocyclyl, optionally substituted with up to 4 substituents selected from R 12, R 13 and R 14; or

(iv)

C 3-7 carbocyclyl, optionally substituted with up to 4 substituents selected from R 12, R 13 and R 14;

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R 9 and R 10 are selected regardless of: hydrogen, hydroxy, alkyl C 1-6 optionally substituted, aryl optionally substituted, aryl (C 1-6) alkyl optionally substituted, an optionally carbocyclic ring substituted 3-7 atoms, heterocyclyl optionally substituted, heterocyclyl (C 1-6) alkyl  optionally substituted or R 9 and R 10 considered together they can form a ring of 3-9 atoms optionally substituted or R 9 and R 10 considered together with the atoms of carbon to which they are attached form a group carbonyl;

R 12

is selected from: hydrogen, hydroxy, R 17 R 18 N (CH 2) cc -, R 17 R 18 NC (O) (CH 2) cc -, (C 1-6) alkyl - C (O) N (R 9) (CH 2) cc - optionally substituted, (C 1-6) alkyl - SO 2 N (R 9) -  optionally substituted, aril-SO 2 N (R 9) - optionally substituted, perfluoroalkyl (C 1-3) - SO 2 N (R 9) -; (C 1-6) alkyl - N (R 9) SO 2 - optionally substituted, aryl-N (R 9) SO 2 - optionally substituted, perfluoroalkyl (C 1-3) - N (R 9) SO 2 -, (C 1-6) alkanoyl - N (R 9) SO 2 - optionally substituted; aryl-C (O) N (R 9) SO 2 - optionally substituted, (C 1-6) alkyl - S (O_n) - optionally substituted, aril-S (O_ {n}) - optionally substituted, C 1-3 perfluoroalkyl, C 1-3 perfluoroalkoxy, alkoxy C 1-6 optionally substituted, carboxy, halogen, nitro or cyano;

R 13 and R 14 are selected Regardless of: hydrogen, hydroxy, oxo, alkyl C 1-6 optionally substituted, alkanoyl C 1-6 optionally substituted, alkenyl C 2-6 optionally substituted, cyano, nitro, C 1-3 perfluoroalkyl, perfluoroalkoxy C 1-3, optionally substituted aryl, aryl (C 1-6) alkyl optionally substituted, R 9 O (CH 2) s -, R 9 (O) O (CH 2) s -, R 9 OC (O) (CH 2) s -, R 16 S (O n) (CH 2) s -, R 9 R 10 NC (O) (CH 2) s - or halogen; A is selected from C 1-5 alkylene optionally substituted, carbonyl or -C (O) -C (R d R d) -, wherein R d is independently selected from hydrogen and I rent C 1-2;

R 17

is independently selected from: hydrogen, hydroxy, cyano or C 1-6 alkyl optionally replaced;

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R 18

it's a formula group R 18a -C (R 9 R 10) 0-1 - wherein R 18a is selected from: R 19 OC (O) -, R 9 R 10 NC (O) -, R 9 R 10 N-, R 9 C (O) -, R 9 C (O) N (R 10) -, R 9 R 10 NC (O) -, R 9 R 10 NC (O) N (R 10) -, R 9 SO 2 N (R 10) -, R 9 R 10 NSO 2 N (R 10) -, R 9 C (O) O-, R 9 OC (O) -, R 9 R 10 NC (O) O-, R 9 O-, R 9 S (O n) -, R 9 R 10 NS (O n) -, hydrogen, C 1-6 alkyl optionally substituted, optionally substituted heterocyclyl; or

R 17 and R 18 when consider together they form a carbocyclic ring optionally substituted 3-7 atoms or heterocyclyl optionally replaced;

R 19

is selected from: hydrogen, alkyl C 1-6 optionally substituted, aryl optionally substituted, aryl (C 1-6) alkyl optionally substituted, C 3-7 cycloalkyl optionally substituted, optionally substituted heterocyclyl or heterocyclyl (C 1-6) alkyl optionally substituted;

B

is selected from C 1-6 alkylene optionally substituted or group

66

quad

form a heterocyclic ring C_ {4-7} optionally substituted, in which the Optional substituents are selected from R 12, R 13 and R 14; the group

67

quad

preferably forms a heterocyclic ring optionally substituted containing 4-7 atoms of carbon, in which the optional substituents are selected from R 12, R 13 and R 14;

K

is selected from: a direct link, - (CH2) s1 -, - (CH 2) s 2 -O- (CH 2) s -, - (CH2) s1 -C (O) - (CH2) s2 -,  - (CH2) s1 - S (O_n) - (CH2) s2 -, - (CH2) s1 -N (R18) - (CH2) s2 -, - (CH 2) s 1 -C (O) N (R 9) - (CH 2) s 2 -, - (CH 2) s 1 -N (R 9) C (O) - (CH 2) s 2 -, - (CH 2) s 1 -N (R 9) C (O) N (R 9) - (CH 2) s 2 -, - (CH2) s1 -OC (O) - (CH2) s2 -, - (CH2) s1 -C (O) O- (CH2) s2 -, - (CH 2) s 1 -N (R 9) C (O) O- (CH 2) s 2 -, - (CH 2) s 1 -OC (O) N (R 9) - (CH 2) s 2 -, - (CH2) s1 -OS (O_n) - (CH2) s2 -,  or - (CH2) s1 -S (O_n) - O- (CH2) s2 -, - (CH2) s1 - S (O) 2 N (R 9) - (CH 2) s 2 -, - (CH2) s1 -N (R9) S (O) 2 - (CH2) s2 -; in which the groups - (CH 2) s 1 - and - (CH2) s2 - are independently optionally substituted with hydroxy, fluoro, cyano, carbamoyl, C 1-4 alkyl and alkoxy C_ {1-4},

n

it is an integer from 0 to 2;

s

it is an integer from 0 to 4;

s1 and s2 are selected regardless of an integer from 0 to 4, and s1 + s2 is less than or equal to 4;

DC

it is an integer from 0 to 2;

or one of its salts, prodrugs or solvates.

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According to another aspect of the present invention, provides a compound of formula (Ic)

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68

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in the that:

R 3 is selected from a group of Formula (IIa) or Formula (IIb):

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69

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and R 1, R 2, R 4, R 5, R 6, R 6a, R 7, R 8, A and B are as they have been definite previously;

or its salts, solvates or prodrugs.

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A more preferred group of compounds of the The invention comprises a compound of formula (Ic), in which:

TO

is C 1-5 alkylene optionally replaced;

B

is selected from C 1-6 alkylene optionally substituted or group

70

quad

form a ring containing heterocyclic ring C 5-7;

R1

it's hydrogen or alkyl C 1-4;

R 6 and R 6a, are selected independently of hydrogen and C 1-6 alkyl optionally replaced;

R 7

is selected from: hydrogen or alkyl C 1-4;

R 8

is selected from hydrogen, cyano, alkyl C 1-6, halogen-alkyl C 1-6, C 2-6 alkynyl, C 1-6 alkanoyl, (C 1-4) alkoxy-(C 1-4) alkyl, (C 1-6) alkoxycarbonyl, N, N-di-(C 1-4) alkyl amino,  aryl, aryl (C 1-6) alkyl, C 3-7 cycloalkyl, (C 3-7) cycloalkyl-(C 1-6) alkyl, heterocyclyl, heterocyclyl (C 1-6) alkyl, or heterocyclylcarbonyl (C 1-4) alkyl in which the aryl and heterocyclyl rings are optionally substituted with cyano and C 1-4 alkyl; Y

R 2, R 4, and R 5; They are as defined previously

or its salts, solvates or prodrugs.

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A more preferred group of compounds of the The invention comprises a compound of formula (Ic), in which:

TO

is C 1-5 alkylene optionally replaced;

B

is selected from C 1-6 alkylene optionally substituted or group

71

quad

form a ring containing heterocyclic ring C 5-7;

R1

is hydrogen or C 1-4 alkyl, preferably hydrogen;

R2

it is a monocyclic aromatic ring structure optionally substituted, preferably optionally phenyl substituted, most preferably 3,5-dimethylfen-1-yl;

R 4

is hydrogen or C 1-4 alkyl, preferably hydrogen;

R 5

is a group of formula (III) in which the group of formula (III) is selected from a group of formula III-a; III-b; III-c; III-d; III-e; III-f, III-g, III-6, III-i ,: III-j, III-k or III-1

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72

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73

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74

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quad

where R 23, R 23a, R 24, R 25 and R 26 are as defined above, preferably the group of formula (III) is selected from (III-a), (III-g) and (III-h);

R 6 and R 6a, are selected independently of hydrogen and C 1-6 alkyl optionally replaced;

R 7

is selected from: hydrogen or alkyl C 1-4;

R 8

is selected from hydrogen, cyano, alkyl C 1-6, halogen-alkyl C 1-6, C 2-6 alkynyl, C 1-6 alkanoyl, (C 1-4) alkoxy-(C 1-4) alkyl, (C 1-6) alkoxycarbonyl, N, N-di-(C 1-4) alkyl amino,  aryl, aryl (C 1-6) alkyl, C 3-7 cycloalkyl, (C 3-7) cycloalkyl-(C 1-6) alkyl, heterocyclyl, heterocyclyl (C 1-6) alkyl, or heterocyclylcarbonyl (C 1-4) alkyl in which the aryl and heterocyclyl rings are optionally substituted with cyano and C 1-4 alkyl; Y

R 2, R 4 and R 5; They are as defined previously

or its salts, solvates or prodrugs.

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A more preferred group of compounds of the The invention comprises a compound of formula (Id):

75

in which R 1, R 2, R 4, R 5; R 7, R 8, A and B are as defined previously

or its salts, solvates or prodrugs.

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A group of compounds of the invention still more preferred comprises a compound of formula (I), (Ia), (Ib), (Ic) or (Id) in which:

R 5 is a group of formula (III) in which the group of formula (III) is a group of formula III-a:

76

in which R 23, R 23a, R 24 and R 25 are as defined above; or one salt, prodrug or solvate of same.

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According to an additional aspect of the invention is provided a compound of formula (I) or (Ia), or its salts, solvates or prodrugs, in which R3 is selected from a group of formula (IIc) or formula (IId) and R 1, R 2, R 4 and R 5 are as defined above.

According to an additional aspect of the invention is provided a compound of formula (I) or (Ia), or its salts, solvates or prodrugs, in which R3 is selected from a group of formula (IIe) or formula (IIf) and R 1, R 2, R 4 and R 5 are as defined above.

According to an additional aspect of the invention is provided a compound of formula (I) or (Ia), or its salts, solvates or prodrugs, in which R3 is selected from a group of formula (IIa), formula (IIc) or formula (IIe) and R1, R 2, R 4 and R 5 are as defined previously.

According to an additional aspect of the invention is provided a compound of formula (I) or (Ia), or its salts, solvates or prodrugs, in which R3 is selected from a group of formula (IIb), formula (IId) or formula (IIf) and R1, R 2, R 4 and R 5 are as defined previously.

A preferred group of compounds according to the Present invention are the compounds selected from:

{(2 S ) -2- (2- [2- (7-azabicyclo (2.2.1] hept-7-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrol-4-yl] propyl} (2-pyridin-4-ylethyl) amine;

2- [2- (7-Azabicyclo [2.2.1] hept-7-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl} -4- {2- [4- (2-morpholin-4-yl-2-oxoethyl) piperazin-1-yl] ethyl} -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [4- (2-hydroxy-3- {4-acetylpiperazin- 1-yl} prop-1-yl) piperazin-1-yl] ethyl-5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4 - [(2- {4- {2-hydroxy-3-piperiazin -1-ylprop-1-yl} piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [2- (7-Azabicyclo [2.2.1] hept-7-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -4- (2- (3- pyridin-4-ylpyrrolidin-1-yl) ethyl] -6 H -thieno [2,3- b ] pyrrole;

2- [2- (7-Azabicyclo [2.2.1] hept-7-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -4- [2- (3- pyridin-2-ylpyrrolidin-1-yl) ethyl] -6H-thieno [2,3-bjpirrol;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {morpholinocarbonyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [2- (7-Azabicyclo [2.2.1] hept-7-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -4- [2- (4- {2.6-dimethylmorpholinocarbonyl} piperidin-1-yl) ethyl] -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [1-oxo-2- {4- (1,1- dioxidotetrahydrotien-3-yl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [1-oxo-2- (4- (pyrrolidin-1- ilcarbonylmethyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [1-oxo-2- {4- (morpholinocarbonyl) piperazin- 1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [1-oxo-2- {3-methyl-4- ( pyrrolidin-1-ylcarbonylmethyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [1-oxo-2-methyl-2- {4- ( 1,1-dioxidotetrahydro-3-thienyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [1-oxo-3- {4- (1,1- dioxidotetrahydro-3-thienyl) piperazin-1-yl} propyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- (pyrrolidin-1-ylcarbonylmethyl) piperazin- 1-yl-ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (2,4-dioxo-1, 2,3,4-tetrahydropyrimidin-6-ylmethyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (6-hydroxypyrid-3-ylmethyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4 - {(3rd R , 6th S ) - tetxahydro-5H- [1,3] dioxolo [4,5-c] pyrrole-5-ylcarbonylmethyl-piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6H-thieno [2,3- b ] pyrrole;

2- (1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (morpholinocarbonyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {N, N-dimethylaminocarbonylmethyl} piperazin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6H-thieno [2,3-b] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [N-isopropylaminocarbonylmethyl) piperazin-1-yl} ethyl] -5 - (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {tetrahydrofuran-2-ylcarbonyl} piperazin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (1,3-dimethyl-2, 4-dioxo-1,2,3,4-tetrahydropyrimidin-6-ylmethyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {piperidin-1-ylcarbonylmethyl} piperazin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl-4- [2- (4- {azetidin-1-ylcarbonylmethyl} piperazin-1 -yl) ethyl] -5- (3,5-dimethylphenyl) -6H-thieno [2,3-b] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4-pyrid-4-ylpiperidin-1-yl ) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2,2.1] heptan-7-yl) ethyl] -4- [2- {4- (1,1-dioxidotetrahydro-3- thienyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (4-acetylpiperazin-1-yl) carbonylpiperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4 - ((3aR, 6aS) -tetrahydro- 3aH-T- [1,3] dioxolo [4,5-c] pyrrol-5-ylcarbonyl) piperidin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3 - b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {morpholinocarbonylmethyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4 - [(2- (4- {tetrahydro-2H-pyran-4 -ylcarbonylamino} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {morpholinocarbonylamino} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {3-oxo-3-morpholinoprop- 1-yl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {isopropylsulfonylaminomethyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {3-hydroxypyrrolidin-1-ylcarbonyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (3-oxo-4- {pyrrolidin-1- ilcarbonylmethyl} piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {4-oxo-4-pyrrolidin- 1-ilbut-3-yl} piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {3-oxo-3-pyrrolidin- 1-ylpmp-2-yl} piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo (2.2.1] heptan-7-yl) ethyl] -4- [2- (4- (pyrrolidin-1-ylcarbonylmethyl} piperazin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4-methoxy-4- {N, N- diethylaminomethyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6H-thieno [2,3-b] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [4- (pyrrolidin-1-ylcarbonylmethyl) piperazin-1-ylmethyl ] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole; Y

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [4- (morpholinocarbonyl) piperidin-1-ylmethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

or one of its salts, prodrugs or Solvates

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An additional preferred group of compounds according to The present invention are the compounds selected from:

{(2 S ) -2- [2- [2- (7-azabicyclo [2.2.1] hept-7-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrol-4-yl] propyl} (2-pyridin-4-ylethyl) amine;

2- [2- (7-Azabicyclo [2.2.1] hept-7-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -4- {2- [4- (2-morpholin-4-yl-2-oxoethyl) piperazin-1-yl] ethyl} -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {morpholinocarbonyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [2- (7-Azabicyclo [2.2.1] hept-7-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -4- (2- (4- {2,6-dimethylmorpholinocarbonyl} piperidin-1-yl) ethyl] -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [1-oxo-2- {4- (1,1- dioxidotetrahydrotien-3-yl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [1-oxo-2-methyl-2- {4- ( 1,1-dioxidotetrahydro-3-thienyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (pyrrolidin-1-ylcarbonylmethyl) piperazin- 1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (2,4-dioxo-1, 2,3,4-tetrahydropyrimidin-6-ylmethyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (morpholinocarbonyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {N, N-dimethylaminocarbonylmethyl} piperazin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [N-isopropylaminocarbonylmethyl] piperazin-1-yl} ethyl] -5 - (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (1,3-dimethyl-2, 4-dioxo-1,2,3,4-tetrahydropyrimidin-6-ylmethyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- (azetidin-1-ylcarbonylmethyl) piperazin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6H-thieno [2,3-b] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- (2- (4-pyrid-4-ylpiperidin-1-yl ) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl)] - 4- [2- (4 - ((3aR, 6aS) -tetrahydro -3aH- [1,3] dioxolo [4,5-c] pyrrol-5-ylcarbonyl) piperidin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {3-hydroxypyrrolidin-1-ylcarbonyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {3-oxo-3-pyrrolidin- 1-ylprop-2-yl} piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole; Y

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {pyrrolidin-1-ylcarbonylmethyl} piperazin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole; Y

or one of its salts, prodrugs or Solvates

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A more preferred group of compounds according to the Present invention are the compounds selected from:

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {morpholinocarbonyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [1-oxo-2-methyl-2- {4- ( 1,1-dioxidotetrahydro-3-thienyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (pyrrolidin-1-ylcarbonylmethyl) piperazin- 1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- (2- {4- (2,4-dioxo-1, 2,3,4-tetrahydropyrimidin-6-ylmethyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {3-hydroxypyrrolidin-1-ylcarbonyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6H-thieno [2,3-b] pyrrole;  Y

2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {3-oxo-3-pyrrolidin- 1-ilprop-2-yl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

or one of its salts, prodrugs or Solvates

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In another embodiment of the invention a group particularly preferred of compounds according to the present invention are the compounds selected from:

N - {2- [2- (1,1-dimethyl-2-oxo-2-pyrrolidin-1-ylethyl) -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole -4-yl] ethyl} -4-pyridin-4-ylbutan-1-amine;

N - {2- [2- [2- (7-azabicyclo [2.2.1] hept-7-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrol-4-yl] ethyl} -4-pyridin-4-ylbutan-1-amine;

N - {2- [2- [2- (7-azabicyclo [2.2.1] hept-7-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrol-4-yl] ethyl} -4-pyridin-4-ylethyl-1-amine;

{(2 S ) -2- [2- [2- (7-azabicyclo [2.2.1] hept-7-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrol-4-yl] propyl} (2-pyridin-4-ylethyl) amine;

N - {2- [2- [2- (2-Azabicyclo [2.2.2] oct-2-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrol-4-yl] ethyl} -4-pyridin-4-ylbutan-1-amine;

N - {2- [2- [2- (2-Azabicyclo [2.2.2] oct-2-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrol-4-yl] ethyl1-4-pyridin-4-ylethyl-1-amine;

{(2 S ) -2- [2- [2- (2-azabicyclo [2.2.2] oct-2-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrol-4-yl] propyl} (2-pyridin-4-ylethyl) amine;

2- (1,1-dimethyl-2-oxo-2-pyrrolidin-1-ylethyl) -5- (3,5-dimethylphenyl) -4- {2- [4- (pyridin-4-ylmethyl) piperazin-1 -yl] ethyl} -6 H -thieno [2,3- b ] pyrrole;

2- (1,1-dimethyl-2-oxo-2-pyrrolidin-1-ylethyl) -5- (3,5-dimethylphenyl) -4- {2- [4- {pyridin-2-ylmethyl) piperazin-1 -yl] ethyl} -6 H -thieno [2,3- b ] pyrrole;

2- (1,1-dimethyl-2-oxo-2-pyrrolidin-1-ylethyl) -5- (3,5-dimethylphenyl) -4- {2- [4-methylpiperazin-1-yl] ethyl} -6 H -thieno [2.3- b ] pyrrole;

2- (1,1-dimethyl-2-ozo-2-pyrrolidin-1-ylethyl) -5- (3,5-dimethylphenyl) -4- {2- [4- (pyridin-4-yl) piperazin-1 -yl] ethyl} -6 H -thieno [2,3- b ] pyrrole;

2- [2- (2-Azabicyclo [2.2.2] oct-2-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -4- (2- (4- methylpiperazin-1-yl) ethyl] -6 H -thieno [2,3- b ] pyrrole;

4- [2- (4-allylpiperazin-1-yl) ethyl] -2- [2- (7-azabicyclo [2.2.1] hept-7-yl) -1,1-dimethyl-2-oxoethyl] -5 - (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole;

2- [2- (7-Azabicyclo [2.2.1] hept-7-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -4- {2- [4- (2-morpholin-4-yl-2-oxoethyl) piperazin-1-yl] ethyl} -6 H -thieno [2,3- b ] pyrrole; Y

2- [2- (7-Azabicyclo [2.2.1] hept-7-yl) -1,1-dimethyl-2-oxoethyl] -5- (3,5-dimethylphenyl) -4- {2- [4- (pyridin-4-ylmethyl) piperazin-1-yl] ethyl} -6 H -thieno [2,3- b ] pyrrole;

or one of its salts, prodrugs or Solvates

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The compounds of formula (I) can be administered in the form of a prodrug that degrades in the human or animal body to provide a compound of formula (I). Examples of prodrugs include in vivo hydrolysable esters of a compound of formula (I).

Different forms of prodrugs For examples of said prodrug derivatives, see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al . (Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs" by H. Bundgaard p. 113-191 (1991);

c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al ., Journal of Pharmaceutical Sciences , 77, 285 (1988); Y

e) N. Kakeya, et al ., Chem. Pharm. Bull ., 32, 692 (1984).

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An in vivo hydrolysable ester of a compound of formula (I) containing a carboxy or hydroxy group is, for example, a pharmaceutically acceptable ester that is hydrolyzed in the human or animal body to produce the original acid or alcohol. Pharmaceutically acceptable esters suitable for carboxy include (C 1-6) alkoxy esters, for example methoxymethyl, alkanoyl (C 1-6) oxymethyl esters, for example pivaloyloxymethyl, phthalidyl esters, esters of (C 3-8) cycloalkoxycarbonyloxy (C 1-6) alkyl, for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, for example 5-methyl-1,3-dioxolen-2-onylmethyl; and esters of (C 1-6) alkoxycarbonyloxyethyl.

An in-vivo hydrolysable ester of a compound of formula (I) containing a hydroxy group or groups includes inorganic esters such as phosphate esters (including cyclic phosphoramyl esters) and α-acyloxyalkyl ethers and related compounds which as a result of hydrolysis In-vivo ester are degraded to provide the original hydroxy group or groups. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of groups that form in vivo hydrolyzable esters for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl) -N-alkylcarbamoyl (to give carbamates ), dialkylaminoacetyl and carboxy acetyl.

A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an addition salt of acid of a compound of the invention that is sufficiently basic, for example, an acid addition salt, for example, a inorganic or organic acid, for example hydrochloric acid, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or Maleic In addition, a suitable pharmaceutically acceptable salt of a compound of the invention that is sufficiently acidic is a salt alkali metal, for example, a sodium or potassium salt, a salt of alkaline earth metal, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base that gives a cation physiologically acceptable, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris- (2-hydroxyethyl) amine.

The compounds of formula (I) can be prepared by a procedure comprising a stage selected from (a) to (i) as follows, and such procedures are provided as a Additional feature of the invention:

(a) Reaction of a compound of formula XXXII with a compound of formula H-R 5 'to form a compound of formula (I),

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wherein X1 is selected from: group

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L 1 is an H-R 5 ' scrollable selected from:

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79

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(b) Reaction of a compound of formula XXXIII with a compound of formula L 2 -R 5 '' to form a compound of formula (I),

80

in which X2 is selected from:

81

L 2 is a movable group and R 7a is select from the definition of R 7 or R 22 above, and

L 2 -R 5 '' is selected of: L 2 -B-R 8, L 2 -J-K-R 8 and L 2 -R 21;

(c) For the compounds of formula (I) in which R 3 is a group of formula (IIa), (IIb), (IIc) or (IId) and R 7 is different from a part of a heterocyclic ring or hydrogen, reaction of a compound of formula (I) in which R 3 is a group of formula (IIa), (IIb), (IIc) or (IId) and R 7 is hydrogen with a group of formula L 3 -R 7a, in which R 7a is as has been defined above for R 7 with the exclusion of hydrogen and L3 is a movable group;

(d) For the compounds of formula (I) in which R 3 is a group of formula (IIe) or (IIf) and R 21 is different of hydrogen, reaction of a compound of formula (I) in which R 3 is a group of formula (IIe) or (IIf) and R 21 is hydrogen with a group of formula L 4 -R 21a, where R 21a is as defined above for R 21 with the exclusion of hydrogen and L 4 is a group scrollable;

(e) For the compounds of formula (I) in which R 3 is a group of formula (IIe) or (IIf) and R 22 is different of hydrogen, reaction of a compound of formula (I) in which R 3 is a group of formula (IIe) or (IIf) and R 22 is hydrogen with a group of formula L 5 -R 22a, wherein R 22a is as defined above for R 22 with the exclusion of hydrogen and L 5 is a group scrollable;

(f) For the compounds of formula (I) in which R 3 is a group of formula (IIc) or (IId) and the group

82

together it forms a heterocyclic ring containing optionally substituted nitrogen containing 4-7 carbon atoms, reaction of a compound of formula XXXIVa or XXXIVb, with a compound of formula L 6 -K-R 8, in which L 6 is a group scrollable

83

(g) For compounds of formula (I) in which R 3 is a group of formula (IIc) or (IId), reaction of a compound of formula XXXVa or XXXVb, with a compound of formula L 7 -K '' - R 8,

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in which L 7 is a movable group, and in which groups K 'and K' 'comprise groups that when they react together they form K,

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(h) reaction of a compound of formula XXXVI with an electrophilic compound of formula L 8 -R 5, in which L 8 is a group scrollable

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85

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(i) reaction of a compound of formula XXXVII with a compound of formula L 10 -R 2, in which L 9 is a group outgoing and L 10 is an activating group or L 9 is a group activator and L 10 is a group outgoing

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86

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and later, if it is necessary:

i) conversion of a compound of formula (I) into another compound of formula (I);

ii) elimination of any group protective;

iii) formation of a salt, prodrug or solvate

The specific reaction conditions for Previous reactions are as follows:

Procedure a) The compounds of formula XXXII and HR 5 'can be coupled together in the presence of an organic base (such as DIPEA [di-isopropylethylamine]) or an inorganic base (such as potassium carbonate), in a suitable solvent such as DMA or DMF, at a temperature of room temperature to 120 ° C. Suitable displaceable groups include: a halide, such as chlorine, or a methanesulfonate or toluenesulfonate;

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Procedure b) The compounds of XXXIII and L 2 -R 5 '' can be coupled together in the presence of an organic base (such as DIPEA) or an inorganic base (such as potassium carbonate), in a suitable solvent such as DMA or DMF, at a temperature of room temperature to 120 ° C. Suitable displaceable groups include: a halide, such as chlorine, or a methanesulfonate or toluenesulfonate,

alternatively, if L 2 is a hydroxy group then L 2 -R 5 '' can be reacted with a compound of formula XXXIII under the reaction conditions from Mitsunobu;

The reaction conditions of the procedures c, d, e and f ) to facilitate these reactions can be using

(i) alkylation reaction conditions or (ii) acylation reaction conditions: Examples of such conditions include:

(i)

alkylation reaction conditions - the presence of an organic base (such as DIPEA) or an inorganic base (such as potassium carbonate), in a suitable solvent such as DMF, DMA, DCM, at a temperature of room temperature at 120 ° C. The right scrollable groups include: a halide, such as chlorine, methanesulfonate or toluenesulfonate;

(ii)

acylation reaction conditions - presence of organic base, such as triethylamine, temperature from 0ºC to 50-60ºC in a suitable solvent such as DCM. The right scrollable groups include acyl chloride or an acid anhydride,

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Procedure g) The person skilled in the art will be familiar with a variety of reaction conditions and values for K 'and K''which, when reacted with each other, form group K, examples of such conditions and values for K' and K '' include:

(i)

For the compounds of formula (1) in which K is - (CH2) s1 -N (R9) C (O) - (CH2) s2 - these they can be prepared by reacting a compound in which K 'is - (CH 2) s 1 -N (R 9) H with a carboxylic acid of formula HOOC- (CH 2) s2 -R8 to form the amide. The coupling of amino groups with carboxylic acids is well known in the art and can be facilitated by a series of chemical reactions using a suitable coupling reagent. For example, a carbodiimide coupling reaction can be performed with EDCl in the presence of DMAP in a suitable solvent such as DCM, chloroform or DMF at room temperature;

(ii)

For the compounds of formula (I) in which K is - (CH2) s1 -C (O) N (R9) - (CH2) s2 - these they can be prepared by reacting a compound in which K 'is - (CH 2) s -COOH with an amine of HN (R 9) - (CH 2) s 2 - R 8 to form the amide. The methodology is the same as the procedures described in (i) earlier in this section;

(iii)

For the compounds of formula (I) in which K is - (CH2) s1 -N (R9) C (O) O- (CH2 ) s2 - these can be prepared by reacting a compound in which K 'is - (CH 2) s 1 -N (R 9) H with a chloroformite of formula ClC (O) O - (CH_ {2) s2 -R8 in a suitable solvent, such as DCM or chloroform, in the presence of a base, such as N- methylmorpholine, pyridine or triethylamine, at a temperature between -10 ° C and 0 ° C;

(iv)

For the compounds of formula (I) in which K is - (CH 2) s 1 -OC (O) N (R 9) - (CH 2) s 2 - these they can be prepared by reacting a compound in which K 'is - (CH 2) s 1 -OC (O) Cl with a compound of formula HN (R 9) - (CH 2) s2 -R8. The methodology is the same as the procedures described in (iii) earlier in this section;

(v)

For the compounds of formula (I) in which K is - (CH 2) s 1 -N ( R 9 ) S (O 2) - (CH 2) s2 - these can be prepared by reacting a compound in which K 'is - (CH 2) s 1 -N (R 9) H with a sulfonyl chloride of the formula ClS (O 2) ) - (CH 2) s 2 -R 8 in the presence of a base, such as triethylamine or pyridine, in a suitable solvent such as chloroform or DCM at a temperature between 0 ° C and room temperature;

(saw)

For compounds of formula (I) in which K is - (CH 2) s 1 -S (O 2) N (R 9) - (CH 2) s2 - these can be prepared by reacting a compound in which K 'is - (CH 2) s 1 -S (O 2) Cl with a compound of HN (R 9) - (CH 2 ) s2 -R8. The methodology is the same as the procedures described in (v) earlier in this section.

(vii)

For compounds of formula (I) in which K is - (CH2) s1 -N (R9) - (CH2) s2 - these can be prepared by making reacting a compound in which K 'is - (CH 2) s 1 -L 11 with a compound of formula HN (R 9) - (CH 2) s 2 -R 8, in which L 11 is a movable group. This reaction can be carried out in the presence of an organic base (such as DIPEA) or an inorganic base (such as potassium carbonate), in a suitable solvent such as DMA or DMF, at a temperature of room temperature to 120 ° C. Suitable displaceable groups include: a halide, such as chlorine, or a methanesulfonate or toluenesulfonate. The compounds can also be prepared by reacting a compound in which K 'is - (CH 2) s 1 -N (R 9) H with a compound of formula L 11 - (CH_ {2) s2 -R8, under the same conditions.

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(viii)

For the compounds of formula (I) in which K is - (CH2) s1 -O- (CH2) s2 - these can be prepared by reacting a compound in which K 'is - (CH 2) s 1 -OH with a compound of formula L 12 - (CH 2) s 2 -R 8, wherein L 12 } is a scrollable group. This reaction can be carried out in the presence of an organic base (such as potassium t- butoxide) or an inorganic base (such as sodium hydride), in a suitable solvent such as DMA or DMF, at a temperature of room temperature to 120 ° C. Suitable displaceable groups include: a halide, such as bromine, or a methanesulfonate or toluenesulfonate. The compounds can also be prepared by reacting a compound in which K 'is - (CH 2) s 1 -L 12 with a compound of formula HO- (CH 2) s 2 -R 8, under the same conditions.

(ix)

For the compounds of formula (I) in which K is - (CH 2) s 1 -C (O) - (CH 2) s 2 - these can be prepared by reacting a compound in which K 'is - (CH 2) s 1 -C (O) -L 13 with a Grignard reagent of formula BrMg (CH 2) s 2 -R 8 , in which L 13 is a movable group. This reaction can be carried out in a non-polar solvent such as THF or diethyl ether at a temperature between room temperature and the boiling point of the solvent. Suitable displaceable groups include: a halide, such as chlorine, or an alkoxide. The compounds can also be prepared by reacting a compound in which K 'is - (CH 2) s 1 -MgBr with a compound of formula L 13 -C (O) - (CH 2) ) s2 -R8, under the same conditions.

Procedure h), the reaction of a compound of formula XXXVI with a compound of formula L 8 -R 5 can be carried out under Friedel Craft conditions, for example in the presence of diethylaluminium chloride in a suitable solvent, such as DCM, in an inert atmosphere such as nitrogen, at a temperature between room temperature and the boiling point of solvent, or under Mannich conditions, for example, formaldehyde and a primary or secondary amine in acetic acid, in an inert atmosphere such as nitrogen at a temperature between room temperature and 100 ° C.

Procedure i), the reaction of a compound of formula XXXVII with a compound of formula L 10 -R 2, wherein L 9 is a leaving group and L 10 is a group activator, or L 9 is an activating group and L 10 is a leaving group, can be carried out in an aprotic polar solvent such as THF, using palladium chemistry under Suzuki or Stille conditions, to a temperature between 0 and 70 ° C.

Those skilled in the art will appreciate that in the procedures of the present invention may be necessary protect some functional groups such as hydroxyl groups or amino in the starting reagents or intermediates by protective groups Therefore, the preparation of the compounds of formula (I) may involve, at a suitable stage, the addition and subsequent elimination of one or more protecting groups.

The protection and unprotection of groups functional is described in "Protective Groups in Organic Chemistry ", edited by J.W.F. McOmie, Plenum Press (1973) and "Protective Groups in Organic Synthesis", 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1991).

A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example, an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example, a methoxycarbonyl, ethoxycarbonyl or tert- butoxycarbonyl group, an arylmethoxycarbonyl group, for example, benzyloxycarbonyl or an aroyl group, for example, benzoyl. The deprotection conditions for the above protective groups necessarily vary with the choice of the protective group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example, lithium or sodium hydroxide. Alternatively, an acyl group such as a tert -butoxycarbonyl group can be removed, for example, by treatment with a suitable acid such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group, for example, by hydrogenation on a catalyst such as palladium on carbon or by treatment with a Lewis acid, for example, boron tris (trifluoroacetate). An alternative suitable protecting group for a primary amino group is, for example, a phthaloyl group that can be removed by treatment with an alkylamine, for example, dimethylaminopropylamine or with hydrazine.

A protective group suitable for a group hydroxy is, for example, an acyl group, for example, a group alkanoyl such as acetyl, an aroyl group, for example, benzoyl or an arylmethyl group, for example, benzyl. The conditions of Check-out for the previous protecting groups will vary necessarily with the choice of the protective group. So by example, an acyl group such as an alkanoyl or aroyl group can removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example, hydroxide of lithium or sodium Alternatively, a group can be deleted. arylmethyl such as a benzyl group, for example, by hydrogenation on a catalyst such as palladium on Coal.

A suitable protecting group for a carboxy group is, for example, an esterifying group, for example, a methyl or ethyl group that can be removed, for example, by hydrolysis with a base such as sodium hydroxide or, for example, a tert group -butyl that can be removed, for example, by treatment with an acid, for example, an organic acid such as trifluoroacetic acid or, for example, a benzyl group that can be removed, for example, by hydrogenation on a catalyst such as palladium on carbon .

Experimental part General reaction schemes

In the following schemes in which Ri, Rii and Riii represent optional substituents on the phenyl ring which are optionally protected when necessary, and R represents a protective group, group C has been represented as a substituted phenyl for the purpose of illustration only. Other C definitions are also suitable.

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Scheme to

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87

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The thienopyrroles, such as 3 can be synthesized by the synthesis reaction of classic Fisher thienopyrroles, by the condensation of a hydrazine-HCl 1 and a ketone 2, which carries hydrogen atoms α to carbonyl (Scheme a). The treatment of these reactants in a suitable solvent, such as acetic acid, ethanol, sec- butanol, toluene, in the presence of an acid, such as sulfuric acid, hydrochloric, polyphosphoric acid and / or a Lewis acid, for example, trifluoride. Boron, zinc chloride, magnesium bromide, at elevated temperatures (for example 100 ° C), gives the desired product. R represents a protecting group, e.g. eg, tert -butyl or phthalimide carbamate.

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(Scheme turns to page next)

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Scheme b

88

Thienopirroles, such as those represented in structure 5, they can also be done using aldehydes 4, which they carry hydrogen atoms α to carbonyl, by cyclization using the above conditions. In this case the substituent in position 2 should be added later (see scheme d).

Scheme C

89

The thienopyrrole can also be synthesized using the Granburg reaction, in which a hydrazine 1 is mixed with the ketone 6, which carries a γ-chlorine atom to the carbonyl, and is heated in a suitable solvent such as ethanol, sec- butanol , toluene at a temperature between 50 ° C and 120 ° C (Scheme c).

Scheme d

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90

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The thienopyrrole 5 can be treated with a "bromine source" such as molecular bromine, pyridinium tribromide, pyrrolidone hydrobromide or equivalent reagents supported on polymer, in an inert solvent such as chloroform, methylene chloride of -10 ° C to 25 ° C to give the 2-bromine compound 8 (Scheme d). Reaction under Suzuki conditions with a palladium catalyst (0), a weak base such as aqueous sodium carbonate or saturated sodium hydrogen carbonate and the like, and a substituted arylboronic acid from commercial or prepared sources (as described in: Gronowitz , S .; Hornfeldt, A.-B .; Yang, Y., - H Chem. Sci . 1986, 26, 311-314), in an inert solvent such as toluene, benzene, dioxane, THF, DMF and the like, with heating between 25 ° C and 100 ° C, preferably 80 ° C, for a period of 1-12 hours, to give the desired compound 3.

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91

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Thiophene 1 can be synthesized by reaction of a hydrazine under the preferred conditions of sodium hydride in DMF at a temperature between -10ºC and -5ºC, followed by reaction with dicarbonate of di-tert-butyl in THF a Reflux.

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Scheme and

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92

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The substituted ketones 2 can be prepared, as indicated in scheme e, starting from suitable acid chlorides such as 9. The treatment of the acid chloride with N, N- dimethylhydroxylamine hydrochloride in the presence of an amine base such as triethylamine, and a suitable solvent such as methylene chloride at a temperature of -10 ° C to 25 ° C, gives amide 10. Then the reaction with a substituted aryl organolithium (prepared essentially as described by Wakefield B, J .; Organolithium Metlwds Academic Press Limited, 1988 , pp. 27-29 and references cited therein) in an inert solvent such as tetrahydrofuran, diethyl ether, benzene, toluene or mixtures thereof and the like, at a temperature between -100 ° C and 0 ° C, and then inactivation of the mixture Reacting with a mineral acid such as hydrochloric acid, give aryl ketone 2.

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Scheme F

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93

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Starting with an easily available amino acid with a suitable chain length [a] 11, the nitrogen atom can be brought to the beginning of the synthesis by the route shown in scheme f. The protection of the amine group of 11 with a tert - butyl carbamate group is achieved by condensation with di- tert-butyl dicarbonate in the presence of an amine base, for example triethylamine, in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran and mixtures thereof and the like, at a temperature of -10 ° C to 25 ° C. The coupling of the acid product with N, N- dimethylhydroxylamine in the presence of a coupling reagent of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) or 1,3-dicyclohexylcarbodiimide (DCC) or the like, with or without 1 -hydroxybenzotriazole (HOBt), and a suitable base, such as triethylamine and the like, in an inert solvent such as methylene chloride, chloroform, dimethylformamide, or mixtures thereof, at or near room temperature for a period of 3 to 24 hours , provided the corresponding coupled product 12. Following the same route described above for scheme e, then the aryl group can be introduced.

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Scheme g

94

Scheme g illustrates another method for synthesis of a ketone such as 2 and 16, in which the nitrogen group  It is introduced at a later stage. As before, an amide of Weinreb 14 can be synthesized from an acid chloride. He treatment with the required amine, in an inert solvent such as THF, toluene, water and the like, can displace group X to give 17. As before, the aryl group can be introduced by displacement of the Weinreb amide with a nucleophile of suitable aryl lithium. Alternatively, the atom of nitrogen can be introduced already protected as a phthalimide, by displacement of group X with potassium phthalimide, or a salt of the same, heating in an inert polar solvent such as DMF, DMSO, THF, toluene with or without the presence of a catalyst such as tetrabutylammonium iodide and the like, to give the compound 15. Again the displacement of Weinreb's amide with an organolytic species completes the synthesis of ketone 16 suitable for cycling under the Fischer conditions described before for the synthesis of thienopyrrole.

Scheme h

95

A procedure can be carried out. alternative for a ketone with phthalimide protected nitrogen, such as 16, first treating a lactone with a species organolytic as in the previous schemes in a solvent suitable such as THF or ether at a low temperature between -100ºC and -50ºC to give the primary alcohol 18 (Scheme h). The hydroxyl function of 18 is replaced by a group phthalimide by a reaction of Mitsunobu with such an activating agent as diethyl diazocarboxylate (DEAD), diazocarboxylate diisopropyl or the like, with triphenylphosphine, tri-butylphosphine and the like, in a solvent inert such as benzene, toluene, tetrahydrofuran or mixtures of the themselves to give the desired ketone 16.

96

If the group R1 was not present in the Starting hydrazine before cyclization to form a thienopyrrole, can be added after cyclization by a alkylation reaction (19 → 3). The thienopyrrole is deprotonates with a strong base, such as sodium hydride, n-butyllithium diisopropylamide lithium, sodium hydroxide, potassium tert-butoxide, in a suitable inert solvent such as THF, DMF, DMSO and the like, and an alkyl halide is added and the mixture is stirred at temperature ambient.

Scheme i

97

Depending on the route used before, a thienopyrrole 20 suitable for conversion to a cyano-guanidine can be formed by removal of the protective group, for example, if a tert - butyl carbamate group was used, then the removal is carried out using a strong acid, for example trifluoroacetic acid or hydrochloric acid in an inert solvent such as methylene chloride chloroform, THF or dioxane at a temperature between -20 ° C and 25 ° C. A phthalimide group, for example, can be removed by hydrazine in a suitable solvent, for example methanol, ethanol, methylene chloride, chloroform, THF, dioxane, at a temperature between -20 ° C and 25 ° C. The primary amine 20 can be converted into a cyano-guanidine 22 by the two-step reaction process with diphenyl cyanocarbonymidate in an inert organic solvent such as isopropyl alcohol, methylene chloride, chloroform, benzene, tetrahydrofuran and the like, at a temperature between -20 ° C and 50 ° C, followed by condensation with a suitably substituted amine in an inert organic solvent from the above list, with heating at a temperature between -20 ° C and 100 ° C (scheme i 20 → 21). Subsequent treatment of 22 with 2 molar hydrochloric acid in methanol at elevated temperature gives guanidine compounds 23.

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Scheme j

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98

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In the same way, the reaction with 1,1'-bis (methylthio) -2-nitroethylene in an inert solvent such as methylene chloride, chloroform, benzene, tetrahydrofuran and the like, followed by condensation with a properly substituted amine in an inert organic solvent from the list above, give the nitroethyleneimidazo [1,2-?] pyridine  25 (scheme j, 20 → 24 → 25).

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Scheme k

99

Again in a similar way, thienopyrrol 20 suitable, obtained from deprotection, can be converted into a urea by direct treatment with an isocyanate in a solvent inert such as methylene chloride, chloroform or THF and the like, or by a two step reaction process with triphosgene (20 → 27) followed by the addition of an amine (27 → 26), which carries the required substitution, to give 26.

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Scheme l

100

The intermediate chloro-thieno-pyrroles, such as 31, can be made as indicated in Scheme 1. The product 30 can be synthesized by the synthesis reaction of classic Fisher thienopyrroles by condensation of a hydrazine-HCl 28 and a ketone 29, which carries hydrogen atoms α to carbonyl. The treatment of these reactants in a suitable solvent, such as acetic acid, ethanol, sec- butanol, toluene, in the presence of an acid, such as sulfuric acid, hydrochloric, polyphosphoric acid and / or a Lewis acid, for example, trifluoride. Boron, zinc chloride, magnesium bromide, at elevated temperatures (for example 100 ° C), gives the desired product. The chlorinated intermediate 31 can then be synthesized from 30 using, for example, (i) sulfonyl chloride in methylene chloride at a temperature of about 0 ° C, or (ii) CCl 4 followed by triphenylphosphine in such a solvent as acetonitrile at a temperature of about 0 ° C. Then, the thienopyrroles of the invention can be prepared by displacement of the chlorine atom using a suitable side chain intermediate product such as a substituted heterocyclic ring.

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Scheme m

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101

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The thienopyrols of formula (I) in which A is a direct bond and R 6 and R 6a are both hydrogen se they can prepare as indicated in scheme m. A thieno-pyrrole 32 can be reacted with formaldehyde and an amine, in a suitable solvent such as acid acetic acid / dioxane at a temperature of approximately 0 ° C to 25 ° C for between about 1 to 8 hours, to form the thieno-pyrrole 34.

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Examples

The invention will now be illustrated with the following non-limiting examples, in which, unless express otherwise:

(i) evaporations were carried out by evaporation in vacuum rotary evaporator and treatment procedures  were carried out after removing residual solids such as the drying agents by filtration;

(ii) the operations were carried out at room temperature, that is in the interval 18-25 ° C and in an atmosphere of such an inert gas as argon or nitrogen;

(iii) returns are provided only for illustrate and are not necessarily the maximums that can be get;

(iv) the structures of the final products of formula (I) were confirmed by nuclear magnetic resonance (NMR) (usually proton) and mass spectroscopy techniques; the values of chemical magnetic resonance shifts of proton were measured on the delta scale and the multiplicities of the peaks are given as follows: s, singlet; d, double up; t, triplet; m multiplet; a, width; q, quartete, quin, quintete;

(v) intermediate products are generally not fully characterized and purity was assessed by analysis of thin layer chromatography (TLC), high liquid chromatography yield (HPLC), infrared (IR) or NMR;

(vi) chromatography was carried out on silica (Merck Keiselgel: Art.9385);

(vii) isolute? refers to columns based on silica (SiO2) with irregular particles with a average size of 50 µm with a nominal porosity of 60 Å [Source: Jones Chromatography, Ltd., Glamorgan, Wales, Kingdom United].

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Abbreviations

DCC

1,3-dicyclohexylcarbodiimide

DCM

dichloromethane

DEAD

diethyl azodicarboxylate

DIPEA

diisopropylethylamine

Dma

dimethylacetamide

DMSO

dimethylsulfoxide

DMAP

4-dimethylaminopyridine

DMF

dimethylformamide

EDCl

hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

HOBt

1-hydroxybenzotriazole

THF

tetrahydrofuran

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Example 1 2- (1,1-Dimethyl-2-oxo-2-pyrrolidin-1-ylethyl) -4- N - (2-pyridin-4-ylethyl) aminoethyl-5- (3,5-dimethylphenyl) -6 H - thieno [2,3- b ] pyrrole

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102

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A solution of compound 14 (0.486 g; 0.649 mmol) in CH 2 Cl 2 (6 ml) was treated with n-propylamine (0.5 ml). The mixture was stirred at room temperature for 1 hour. After evaporation at dryness, the residue was taken up in AcOEt and treated at 0 ° C with a HCl / ether mixture to give a precipitate that was washed with AcOEt and ether.

Yield: 81%

ESI-MS: 515 [M + H] + 1 H NMR (DMSOd 6): 1.55 (s, 6H); 1.64 (m, 4 H); 2.33 (s, 6H); 3-3.5 (m, 12H); 9.89 (s, 1 H); 6.95 (s, 1 H); 7.08 (s, 2H); 7.6-7.9 (broad m, 1H); 8.04 (d, 2H); 8.93 (d, 2H).

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The starting material was prepared as follow:

103

To a suspension of NaH (54 g; 1.35 mol) and 18-crown-6 in THF (21) stirred at room temperature under argon, the compound was added 1 (100 g; 0.588 mol) over a period of 30 minutes. After stirring overnight, the mixture was cooled to 0 ° C and added dropwise methyl iodide. The mixture was stirred at 18 ° C for 3 hours, it was poured into a saturated NH4Cl solution and extracted with AcOEt. The organic phase was evaporated and purified by Instant chromatography eluting with petroleum ether / acetate ethyl 95/5 to give compound 2 as an oil.

Yield: 90%

1 H NMR (CDCl 3): 1.20 (t, 3H); 1.63 (8s, 6H); 4.10 (q, 2H); 6.92 (m, 2H); 7.17 (m, 1 H).

Nitronium tetrafluoroborate (77.9 g; 0.586 mol) at -55 ° C to a solution of compound 2 (105.6 g; 0.583 mol) in DME (1.51). The mixture was allowed to warm to -10 ° C over 4 hours. After extracting with ethyl acetate, the organic phase was purified by chromatography instant, eluting with petroleum ether / AcOEt 95/5 to give the compound 3.

Yield: 86%

1 H NMR (CDCl 3): 1.23 (t, 3H); 1.65 (s, 6H); 4.14 (q, 2H); 6.90 (d, 1 H); 7.75 (d, 1 H).

A suspension of compound 3 (101.7 g; 0.41 mol) and 10% Pd / C (15 g) in a mixture of ethanol (700 ml) and ethyl acetate (300 ml) was hydrogenated under hydrogen atmosphere (5 bars) for 5 hours. After filtering the catalyst over Celite, the residue was evaporated and re-dissolved in THF (900 ml); dicarbonate of di-tert-butyl (100 g; 0.46 mol) and The mixture was refluxed for 16 hours. After evaporating  the solvents, the resulting solid was collected in ether of oil and filtered to give compound 5.

Yield: 68%

1 H NMR (CDCl 3): 1.20 (t, 3H); 1.48 (s, 9H); 1.58 (s, 6H); 4.10 (q, 2H); 6.30 (m, 1 H); 6.60 (m, 1 H).

A solution of compound 5 (50 g; 0.16 mol) and 2N NaOH (160 ml) in ethanol (300 ml) was refluxed for 1 h 30. After evaporation to dryness, the residue was partitioned between water and ether. The aqueous layer was acidified with citric acid. saturated and extracted with ethyl acetate to give after evaporation a solid, which was triturated in pentane and filtered to give compound 6 as a solid.

Yield: 100%

1 H NMR (DMSOd 6): 1.48 (m, 15H); 6.30 (d, 1 H); 6.59 (d, 1 H).

A solution of compound 6 (20.1 g; 0.07 mol), EDCl (20.1 g; 0.105 mol) and DMAP (2.56 g; 0.021 mol) in dichloromethane  (200 ml) was stirred under argon for 10 minutes. After pyrrolidine (11.69 ml; 0.14 mol) was added and the mixture was stirred overnight at room temperature. After evaporation at dryness, the residue was purified by flash chromatography eluting with AcOEt / petroleum ether 40/60 to give after the trituration in ether / pentane compound 7 in the form of a solid.

Yield 73%

1 H NMR (CDCl 3): 1.51 and 1.57 (s, 15 H); 1.7 (m, 4H); 3.03 (width, 2H); 3.50 (width, 2H); 6.35 (d, 1 H); 6.48 (d, 1 H); 7.26 (width, 1H).

Compound 7 (17 g; 0.05 mol) was added in Argon atmosphere at a suspension of 60% NaH (2.42 g; 0.06 mol) in dioxane (240 ml). The mixture was stirred at 100 ° C for 3 hours. After cooling to 10 ° C, compound 8 (10.1 g; 0.055 mol). The reaction mixture was stirred at room temperature. during one night After filtering the insoluble material, the filtrate was evaporated and purified by flash chromatography, eluting with AcOEt / petroleum ether 45/55 to give 9 in the form of a white solid

Yield: 90%

1 H NMR (CDCl 3): 1.55 and 1.57 (s, 15 H); 1.71 (s, 4H); 3.04 (s, 2H); 3.50 (s, 2 H); 6.53 (d, 2H); 6.70 (s, 2H).

A solution of the hydrochloride salt of compound 9 (4 g; 0.0102 mol) and compound 10 (6.6 g; 0.0205 mol) in AcOH (20 ml) it was heated at 120 ° C under an argon atmosphere for 3 hours. The reaction mixture was diluted with saturated solution of NH4Cl and extracted with AcOEt. After evaporation, the crude product was purified by flash chromatography eluting with 50/50 AcOEt / petroleum ether to give compound 11 in the form of a foam.

Yield: 53%

1 H NMR (CDCl 3): 1.53 and 1.58 (s, 6H); 1.69 (s, 4 H); 2.29 (s, 6H); 3.12 (m, 4H); 3.52 (s, 2H); 3.91 (m, 2H); 6.80 (m, 2 H); 7.02 (s, 2H); 7.6-7.8 (m, 4H); 8.10 (s, 1 H). ESI-MS: 540 [M + H] +

A solution of compound 11 (0.534 g; 0.99 mmol) and hydrazine (1 ml) in a mixture of EtOH (2 ml) and CH 2 Cl 2 (2 ml) was stirred under argon to room temperature overnight. After evaporation, the crude product was extracted in a mixture of CH 2 Cl 2 and saturated NaHCO3 solution. The organic layer was evaporated to give compound 12 in the form of a foam.

Yield: 90%

1 H NMR (CDCl 3): 1.52 and 1.62 (s, 6H); 1.69 (s, 4 H); 2.33 (s, 6H); 2.80-3.2 (m, 6H); 3.52 (m, 2H); 6.74 (s, 1 H); 6.93 (s, 1 H); 7.05 (s, 2H); 8.15 (s, 1 H).

EM-ESI: 410 [M + H] +

2,4 dinitrobenzyl sulfonyl chloride was added (0.238 g; 0.892 mmol) at 0 ° C, under argon at a solution of compound 12 (0.365 g; 0.882 mmol) and collidine (0.118 ml; 0.892 mmol) in CH 2 Cl 2 (5 ml). The mixture was stirred at 20 ° C for 1 hour. After evaporation, the crude product was purified by flash chromatography eluting with CH2Cl2 / EtOH 96/4 to give compound 13.

Yield: 90%

EM-ESI: 640 [M + H] +

DEAD (0.295 ml; 1.5 mmol) was added at 0 ° C in Argon atmosphere to a solution of compound 13 (0.48 g; 0.75 mmol), PPh3 (0.393 g; 1.5 mmol) and 2-hydroxyethyl-4-pyridine (0.185 g; 1.5 mmol) in THF (12 ml). The mixture was stirred at room temperature for 2 hours and purified by chromatography instant eluting with 80/20 AcOEt / petroleum ether to give the compound 14. Yield: 86%

1 H NMR (CDCl 3): 1.55 (s, 6H); 1.55-1.8 (m, 4H); 2.3 (s, 6H); 2.75 (t, 2H); 3-3.2 (m, 4H); 3.4-3.7 (m, 6H); 6.71 (s, 1 H); 6.88 (d, 2H); 6.93 (s, 1 H); 6.94 (s, 2H); 7.86 (d, 1 HOUR); 8.20-8.25 (m, 2H); 8.31 (s, 1 H); 8.43 (d, 2H).

Examples 1.1-1.12

Following a procedure similar to that described in example 1, the compounds of Table 1 were prepared and purified by flash chromatography eluting with a gradient of NH 3 3.5 N-MeOH / CH 2 Cl 2 al 0-5%

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TABLE 1

104

105

106

Example 2 2- (1,1-Dimethyl-2-oxo-2-pyrrolidin-1-ylethyl) -4- {2- [1- (pyridin-3-ylmethyl) piperazin-4-yl] ethyl} -5- (3 , 5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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107

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A mixture of compound 16 (0.362 g; 0.844 mmol), compound 17 (0.3 g; 1.68 mmol), K 2 CO 3 (0.233 g; 1.68 mmol) in acetonitrile (6 ml) was heated at 85 ° C under an atmosphere of Argon for 5 hours. The mixture was extracted with AcOEt and the layer Organic was evaporated and purified by flash chromatography, eluting with CH 2 Cl 2 NH 3 3.5 N in MeOH 95/5 to give after trituration with ether-pentane, the compound of example 2 in the form of a solid.

Yield: 62%

EM-ESI: 570 [M + H] +

1 H NMR (CDCl 3): 1.64 (s, 6H); 1.6-1.7 (broad m, 4H); 2.34 (s, 6H); 2.4-2.8 (m, 10H); 2.9-3 (m, 2H); 3.1-3.2 (m, 2H); 3.45-3.65 (m, 4H); 6.74 (s, 1 H); 6.94 (s, 1 H); 7.05 (s, 2H); 7.67 (d, 2H); 8.2 (s, 1 HOUR); 8.5 (d, 2H).

The starting material was prepared as follow:

A solution of the hydrochloride salt of compound 9 (2 g; 0.005 mol), and compound 15 (2.16 g; 0.01 mol) in sec-butanol (5 ml) was heated at 105 ° C in atmosphere of argon for 2 hours and at 60 ° C overnight. Solvent it was evaporated and the residue was purified by flash chromatography eluting with petroleum ether / AcOEt 60/40 to give the compound 16.

EM-ESI: 429 [M + H] +

1 H NMR (DMSO d 6): 1.53 (s, 6H); 1.64 (broad m, 4H); 2-2.15 (m, 1 H); 2.3 (s, 6H); 2.4-2.5 (broad m, 1H); 3-3.10 (m, 4H); 3.35-3.5 (m, 7H); 3.8 (broad m, 2H); 6.83 (s, 1 HOUR); 6.91 (s, 1 H); 7.09 (s, 2H).

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Examples 2.1-2.41

Following a procedure similar to that described In Example 2, the compounds of Table 2 were prepared.

TABLE 2

108

109

110

111

112

113

114

115

The compound of Example 2.9 was obtained by deprotection of the compound of example 2.8 in the presence of TFA in methylene chloride

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Example 3 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (2-hydroxy-3 - {( 3rd R , 6th S ) -tetrahydro-5 H - [1,3] dioxolo [4,5- c ] pyrrol-5-yl} -prop-1-yl) piperazin-1-yl} ethyl] -5- ( 3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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116

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A mixture of compound 19 (0.187 g; 0.33 mmol), hydrochloride salt of amino compound 20 (0.152 g; 1.00 mmol) and triethylamine (0.134 ml; 1.00 mmol) in ethanol (2 ml) is heated to reflux for 2 hours. The mixture was concentrated and purified by flash chromatography, eluting with CH 2 Cl 2 / NH 3 3.5 N in MeOH 100/0 to 90/10 to give after trituration with ether-pentane the compound of example 3 in the form of a white solid.

Yield: 40%

EM-ESI: 676 [M + H] +

1 H NMR (CDCl 3): 1.25-1.31 (m, 4H); 1.50-1.71 (m, 4H); 1.62 (s, 6H); 2.24 (d, 1 H); 2.32 (m, 1 H); 2.35 (s, 6H); 2.38-2.63 (m, 12H); 2.68 (m, 2 H); 2.93 (m, 2H); 3.18 (d, 2H); 3.84 (m, 1 H); 4.11 (broad s, 1H); 4.58 (s, 2 H); 4.72 (s width, 1H); 4.92 (s, 1 H); 5.09 (s, 1 H); 6.74 (s, 1 H); 6.94 (s, 1 H); 7.06 (s, 2H); 8.13 (s, 1 H).

Compound 19 was prepared as follows:

To a mixture of compound 18 (1.75 g; 3.4 mmol) and K 2 CO 3 (0.55 g; 4.0 mmol) in dimethylacetamide (15 ml) is added epibromhydrin (0.35 ml; 4.0 mmol). The mixture was heated to 85 ° C under argon for 6 hours. After cooling, it Water was added and the mixture was extracted with AcOEt. The organic layer is washed with brine, dried with MgSO4, evaporated and purified by flash chromatography, eluting with CH2Cl2 MeOH 95/5 to 93/7 to give compound 19 in the form of a foam orange.

Yield: 78%

EM-ESI: 561 [M + H] +

1 H NMR (CDCl 3): 1.31-2.17 (m, 14H); 2.35 (s, 6H); 2.17-2.33 (m, 2H); 2.49-2.79 (m, 12H); 2.94-3.11 (m, 2H); 3.11 (m, 1 H); 4.23 (m width, 1H); 4.51 (broad m, 1H); 6.75 (s, 1 H); 6.94 (s, 1 H); 7.07 (s, 2H); 8.14 (broad m, NH).

The synthesis of compound 18 is described in the example 11.

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Examples 3.1-3.11

Following a procedure similar to that described In Example 3, the compounds of Table 3 were prepared.

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TABLE 3

117

118

119

Example 4 2- (1,1-Dimethyl-2-oxo-2-pyrrolidin-1-ylethyl) -5- (3,5-dimethylphenyl) -4- [2- (3-pyridin-4-ylpyrrolidin-1-yl) ethyl] -6 H -thieno [2,3- b ] pyrrole

120

A mixture of compound 16 (0.3 g; 0.7 mmol), 4-pyrrolidin-3-yl-pyridine (0.31 g, 2.1 mmol), K2CO3 (0.29 g; 2.1 mmol) and NaI (0.314 g; 2.1 mmol) in acetonitrile (10 ml) was heated at 70 ° C in atmosphere of argon for 20 hours. The mixture was extracted with CH 2 Cl 2 and the organic layer was evaporated and purified by instant chromatography eluting with a gradient of 5-10% MeOH / CH 2 Cl 2 to give the compound  from example 4 in the form of a solid.

Yield: 40%

EM-ESI: 541 [M + H] +

1 H NMR (CDCl 3): 1.63 (s, 6H); 1.6-1.75 (broad m, 4H); 1.75-1.95 (m width, 1H); 2.31 (s, 6H); 2.3-2.35 (broad m, 1H); 2.58 (m, 1 H); 2.7-3.2 (m, 9H); 3.25-3.35 (m, 1 H); 3.4-3.6 (m, 2H); 6.74 (s, 1 H); 6.91 (s, 1 H); 7.05 (s, 2H); 7.15 (d, 2H); 8.46 (d, 2H); 8.53 (s, 1 H).

Examples 4.1

Following a procedure similar to that described In Example 4, the compound of Example 4.1 was prepared.

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TABLE 4

121

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Example 5 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {morpholinocarbonyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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A mixture of compound 29 (0.137 g; 0.3 mmol), compound 30 (0.150 g, 0.6 mmol), K 2 CO 3 (0.125 g; 0.9 mmol) and NaI (0.045 g; 0.3 mmol) in dimethylacetamide (3 ml) is heated at 85 ° C under argon for 6 hours. Mix Gross was purified on preparative LC-MS (column Symetry C 18, AcOH buffer, gradient H 2 O-CH 3 CN) and the residue was evaporated and crystallized from a mixture of pentane-Et2O to give the compound of example 5 in the form of a white solid.

Yield: 55%

EM-ESI: 617 [M + H] +

1 H NMR (CDCl 3): 1.28 (m, 4H); 1.62 (s, 6H); 1.50-1.75 (m, 6H); 1.93 (m, 2 H); 2.08 (m, 2H); 2.35 (s, 6H); 2.48 (m, 1 H); 2.68 (m, 2 H); 2.97 (broad s, 2H); 3.09 (m, 2H); 3.50 (s, 2 H); 3.62 (s, 2H); 3.68 (s, 4 H); 4.12 (wide s, 1 HOUR); 4.75 (broad s, 1H); 6.75 (s, 1 H); 6.94 (s, 1 H); 7.06 (s, 2H); 8.13 (s, 1 H).

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Intermediate 29 was prepared as follow:

123

To a suspension of sodium hydride (44.6 g; 1.12 mol) in DMF (700 ml) at 10 ° C, a solution of compound 5 was added (290 g; 930 mmol) in DMF (1 liter) over a period of 5 minutes The resulting orange suspension was allowed to warm to room temperature and stirred for 2 hours. The solution resulting was cooled to -5 ° C in an acetone / ice bath and a solution of compound 8 (201 g; 1.02 mol) in DMF was added (1.41) over a period of 1 hour. During this period it added additional DMF (1 liter) to mobilize the thick precipitate That formed. The resulting suspension was allowed to warm to room temperature and stirred overnight, after which HPLC showed no remaining starting material. The suspension is poured into water (6 liters) and extracted with diethyl ether (3x2 liters) The organic extracts were combined and concentrated to approximately 3 liters and washed with water (4x1.5 liters), a saturated brine solution (1 liter), dried over sulfate magnesium and evaporated to dryness to provide the base free in the form of a whitish solid with performance quantitative. To a stirred solution of the free base (150 g; 457 mmol) in diethyl ether (1.2 liters) and heptane (600 ml) at 0 ° C, added a solution of 4.0 M HCl in 1,4-dioxane (145 ml; 570 mmol) over a period of 1 hour. He resulting thick white precipitate was collected by filtration, washed with a mixture of diethyl ether-heptane (1: 1, 500 ml) and dried to a constant weight to provide the compound 21.HCl (160.3 g) in the form of a white solid.

Yield: 96%

EM-ESI: 328 [M + H] +

To a stirred solution of compound 21 (141 g; 380 mmol) in 2-butanol (1.3 liters) the compound 22 (104 g; 540 mmol) and zinc chloride (106 g; 770 mmol). The resulting suspension was heated at 100 ° C for 8 hours later. of which the HPLC showed that there was no starting material left. The resulting dark brown solution was evaporated to dryness in a rotary evaporator The resulting dark brown residue was dissolved in DCM (100 ml), filtered and the filtrate was purified by chromatography instant eluting with DCM, ethyl acetate (9: 1) to provide compound 23 (98 g) as a solid Brown.

Yield: 67%

EM-ESI: 386 [M + H] +

To a stirred solution of compound 23 (98 g; 254 mmol) in ethanol (1.8 liters) 1N NaOH (1.27 liters, was added, 1270 mmol). The resulting solution was heated at 60 ° C for 4 hours. after which the HPLC showed that there was no material left departure. The reaction mixture was cooled to room temperature and the Ethanol was separated on a rotary evaporator. The resulting brown solution is cooled to 5 ° C and concentrated HCl was added dropwise with stirring rapidly reducing the pH to 1. The resulting precipitate was collected by filtration, washed at a neutral pH with water (3x1 liter) and dried to a constant weight in a vacuum oven at 50 ° C to provide compound 24 in the form of a beige solid (68.3 g).

Yield: 75%

EM-ESI: 358 [M + H] +

To a stirred solution of compound 24 (35.7 g; 100 mmol) and compound 27 (57 g; 150 mmol) in DCM (1 liter) at At 0 ° C, DIPEA (70 ml; 400 mmol) and solid HATU (57 g; 150 mmol) over a period of 15 minutes. Reaction mixture it was allowed to warm to room temperature and stirred for 2 hours, after which the HPLC showed that there was no material left departure. The reaction mixture was washed with an aqueous solution. saturated citric acid (350 ml), a saturated solution of baking soda (350 ml) and water (3 x 350 ml). Organic layer dried over anhydrous magnesium sulfate, filtered, and evaporated until dry on a rotary evaporator. The resulting oily residue is triturated with ethyl acetate (100 ml) and the resulting precipitate was collected by filtration and dried to a constant weight in a vacuum oven at 40 ° C to provide compound 28 (31.4 g) in Shape of a beige solid.

Yield: 69%

EM-ESI: 437 [M + H] +

To a stirred solution of compound 28 (29.7 g; 68.1 mmol) in DCM (700 ml) at 0 ° C was added dropwise pure thionyl (6 ml; 81.7 mmol). The reaction mixture was left. heat to room temperature and stirred for a period of 2 hours, after which the HPLC showed that there was no material left departure. The reaction mixture was evaporated and purified by flash chromatography, eluting with methylene chloride, AcOEt (9: 1) to give compound 29 in the form of a beige foam. The foam was triturated with diethyl ether (100 ml) and the solid resulting was collected by filtration, washed with diethyl ether (2 50 ml) and dried to a constant weight in a vacuum oven at 40 ° C to provide compound 29 in the form of a white solid (26.5 g).

Yield: 85%

EM-ESI: 454 [M + H] +

1 H NMR (DMSO-d 6) 1.19-1.41 (m, 4H); 1.45-1.59 (m, 10H); 2.32 (s, 6H); 3.14 (t, 2H); 3.83 (t, 4H); 4.13 (broad s, 1H); 4.43 (broad s, 1H); 6.89-6.93 (two s that overlap, 2H); 7.08 (s, 2H).

Intermediate amine 27 was synthesized as follow:

124

To an agitated suspension of trans-4-aminocyclohexanol (300 g; 1.98 mol) in isopropanol (3.5 liters) at 0 ° C triethylamine was added (1.1 liter; 7.92 mol) followed by solid p-toluenesulfonyl (377 g; 1.98 mmol) at over a period of 30 minutes. The reaction mixture was heated. at 60 ° C for 2 hours, after which HPLC showed no Starting material remained. The resulting suspension was cooled to room temperature and hydrochloride precipitate of Triethylamine was filtered off. The filtrate was evaporated at dry on a rotary evaporator to provide a colorless oil that dissolved in ethyl acetate (3 liters), washed with 0.5 N HCl (800 ml), water (1.5 liters) and dried over MgSO4. The solvent is evaporated in a rotary evaporator to provide compound 25 (456.5 g) in the form of a white crystalline solid.

Yield: 86%

EM-ESI: 270 [M + H] +

To a stirred solution of compound 25 (600 g; 2.23 mol) in THF (2 liters) at -10 ° C in a bath ice / acetone, triphenylphosphine (700 g; 2.67 mol) was added followed of azadicarboxylate di-tert-butyl (DTBAD) (564 g; 2.45 mol) in THF (1.5 liters) over a period of 1.5 hours keeping the indoor temperature below 10 ° C. The bathroom of ice / acetone was removed and the reaction mixture was allowed to warm to room temperature over a period of 1.5 hours, after of which HPLC showed that there was no starting material left. The reaction mixture was evaporated to dryness and the residue crystallized in hot MeOH (2.8 liters). The resulting crystalline suspension it was cooled to 0 ° C and the crystals were collected by filtration, washed with cold MeOH (2 x 200 ml) and dried to a weight constant in a vacuum oven to provide compound 26 (378.2 g) in the form of a white crystalline solid usually contaminated with approximately 10% (w / w) of oxide triphenylphosphine Yield: 68%

EM-ESI: 252 [M + H] +

In two separate batches: To a stirred solution of compound 26 (380 g; 1.51 mol) in THF (3 liters) at 0 ° C added solid pellets of lithium aluminum hydride (229.4 g; 6.04 mol) over a period of 2 hours under a layer of nitrogen. The resulting gray suspension was allowed to warm to room temperature and stirred for 4 days, after which HPLC showed no remaining starting material. The mixture of reaction was diluted with THF (1 liter), cooled to 0 ° C and added solid sodium sulfate decahydrate over a period of 2 hours with rapid agitation. When the effervescence decreased, the resulting suspension was filtered and the filtrate was acidified with HCl gas providing a thick white precipitate that was collected by filtration, washed with THF (2 x 500 ml) and dried to a weight constant to provide compound 108 (lot 1: 86.8 g; 43%) (lot 2: 97.3 g; 49%) in the form of a white solid. The cakes of filtration obtained from the first filtration were suspended in 6 N NaOH (400 ml) and filtered. The filtrate was extracted with ether diethyl (4 liters). The organic layer was acidified with gaseous HCl providing a thick white precipitate that was collected by filtration, washed with diethyl ether (2 x 500 ml) and dried until a constant weight in a vacuum oven at 40 ° C to provide the compound 27.HCl (105.9 g) in the form of a white solid.

Yield: 72%

1 H NMR (DMSO-d 6) 1.57 (m, 4H); 1.86 (m, 4 H); 4.12 (s, 2H); 8.80-9.05 (s wide, 1H).

Examples 5.1-5.3

Following a procedure similar to that described In Example 5, the compounds of Table 5 were prepared.

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TABLE 5

125

Example 6 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [1-oxo-2- {4- (1,1- dioxidotetrahydrotien-3-yl) piperazin-1-yl] ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3 b ] pyrrole

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126

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Was added 1- (tetrahydro-1,1-dioxide-3-thienyl) -piperazine (0.044 g, 0.22 mmol) to a stirred solution of compound 31 (0.050 g, 0.11 mmol), catalytic NaI and diisopropylethylamine (93 µl, 0.55 mmol) in DMF (3 ml). After stirring for 2 h at 90 ° C in nitrogen atmosphere, the reaction mixture was evaporated to dryness under reduced pressure. The residue was partitioned between DCM and water, the Organic extracts were washed with brine, dried and dried. evaporated to dryness. The crude product was purified by silica chromatography, eluting with MeOH / DCM at 0-10% to give the compound of example 6 in form of a yellow foam (0.054 g), Yield: 79%

ESI-MS : 637 (M + + H).

1 H NMR (DMSOd 6) 1.20-1.40 (m, 4H), 1.47-1.80 (m, 10H), 2.00-2.19 (m, 1H) , 2.37 (s, 6H), 2.44-2.65 (m, 9H), 2.90-3.10 (m, 2H), 3.15-3.29 (m, 3H), 3 , 42 (s, 2H), 4.00-5.00 (m, 2H), 7.06 (s, 1H), 7.14 (m, 3H), 8.86 (s, 1H)

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The starting material 31 was prepared as follow:

A 1.0 M solution of diethyl aluminum chloride in hexanes (25 ml; 25 mmol) was added dropwise to a solution cooled of compound 32 (2.0 g; 5.1 mmol) in stirred DCM (150 ml) in a nitrogen atmosphere at -20 ° C. The reaction * is allowed to warm to 0 ° C and kept at this temperature for 30 min. It was then cooled again to -20 ° C and chloride was added. of chloroacetyl (3.4 g; 30 mmol) and then the reaction was heated to room temperature and stirred for two more hours. Turned to cool to -20 ° C and water (20 ml) was added with care of so that the temperature did not rise above -10 ° C. It was then heated to room temperature and the organic components, dried and evaporated to dryness at reduced pressure The residue was purified on a silica column snapshot eluted with 10-20% EtOAc / DCM and then EtOAc to give compound 31 (1.35 g) as a pale yellow solid.

ESI-MS : 469.13, 471.12 (M + + H).

1 H NMR (DMSOd 6) 1.54-1.64 (m, 8H), 1.70 (s, 6H), 2.46 (s, 6H), 4.34-4.56 (m, 2H), 4.70 (m, 2H), 7.23 (s, 2H), 7.33 (s, 2H), 12.45 (wide s, 1H).

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Compound 32 was prepared as follows:

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128

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To a stirred solution of compound 33 (20.75 g, 50 mmol), 3,5-dimethylacetophenone (7.5 g, 50 mmol) and anisole (25 ml) in 2-butanol (25 ml) are slowly added a solution of 4M HCl in dioxane (15 ml). The mixture was heated to reflux for 30 minutes. After evaporate the solvents, the crude product was precipitated in AcOEt, filtered and washed with EtOAc. This gross product is purified by flash chromatography eluting first with a AcOEt / methylene chloride gradient 25/75 to 50/50 and then a MeOH / AcOEt / methylene chloride gradient 10/40/50 to give after trituration in methylene chloride compound 32 in form of a pale brown solid.

Yield: 19%

EM-ESI: 393 [M + H] +

Compound 33 was prepared following a procedure similar to that described to prepare the product Intermediate 9 (see example 1).

1 H NMR (CDCl 3): 1.32 (m, 4H); 1.52 (s, 9H); 1.56 (s, 6H); 1.50-1.61 (m, 4H); 4.00-5.00 (broad m, 1H + 1H); 6.60 (s, 1 H); 6.94 (s, 1 HOUR).

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Examples 6.1-6.31

Following a procedure similar to that described in example 6, the compounds of table 6 were prepared.

129

130

131

132

133

134

135

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The new intermediate products used in the Coupling synthesis were prepared as follows:

136

MCPBA (2.44 g, 9.88 mmol) was added to a stirred solution of compound 34 (1,075 g, 3.95 mmol) [see intermediate for example 6.11] in DCM (15 ml) at 0 ° C in nitrogen atmosphere After stirring for 15 min at 0 ° C the reaction was quenched by the addition of saturated aqueous solution of sodium metabisulfite (20 ml). The phases and the phase were separated Organic was washed with saturated sodium bicarbonate solution (20 ml), saturated brine (20 ml), dried and evaporated to dryness under reduced pressure.

The residue was purified by chromatography on silica, eluting with 20% DCM / EtOAc followed by MeOH / DCM at 0-5% to give compound 36 as a solid yellow (0.070 g) and compound 35 in the form of a colored solid cream (0.65 g).

Compound 35

ESI-MS : 289 (M + + H).

1 H NMR (CDCl 3) 1.48 (s, 9H), 1.70-1.90 (m, 1H), 2.00-2.18 (m, 1H), 2.69 (d, 1H), 2.73-3.30 (m, 10H), 3.45-3.80 (m, 2H).

Compound 36

ESI-MS : 305 (M + + H).

1 H NMR (CDCl 3) 1.40-2.15 (m, 11H), 2.93-3.20 (m, 6H), 3.21-3.78 (m, 7H) .

1.0M HCl in Et2O (5 mL, 5.0) was added mmol) to a solution of compound 36 (0.122 g, 0.40 mmol) in DCM (2 ml). After stirring at room temperature for 16 h it evaporated the solvents under reduced pressure to give the compound 37 in the form of a yellow solid (0.097 g).

ESI-MS : 205 (M + + H).

137

1.0M HCl in Et2O (5 mL, 5.0) was added mmol) to a solution of compound 35 [see intermediate for example 6.8] (0.1 g, 0.35 mmol) in DCM (1 ml). After Stir at room temperature for 16 h. solvents under reduced pressure to give compound 38 in the form of a pale yellow solid (0.078 g).

ESI-MS : 189 (M + + H).

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138

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Methanesulfonate of N- (tert (butoxycarbonyl) -3-hydroxypyrrolidine (2.0 g, 7.55 mmol) to a solution of thiomorpholine (4 ml, 39.8 mmol) in DMF (4 ml). After stirring at reflux (153 ° C) under an atmosphere of nitrogen for 30 min the reaction mixture was allowed to cool and evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica, eluting with MeOH / DCM at 0-10% to give compound 34 in the form of a brown solid (2.1 g).

ESI-MS : 274 (M + + H).

1 H NMR (CDCl 3) 1.47 (s, 9H), 1.65-1.85 (m, 1H), 1.86-2.12 (m, 2H), 2.54 -3.00 (m, 4H), 3.02-3.16 (m, 1H), 3.19-3.32 (m, 1H), 3.40-3.73 (m, 4H), 3 , 78-3.85 (m, 2H).

1.0 M HCl in Et2 0 (8 ml, 8.0 was added mmol) to a solution of compound (27) (0.695 g, 2.55 mmol) in DCM (2 ml). After stirring at room temperature for 16 h it evaporated the solvents under reduced pressure to give the compound (28) in the form of a pale brown solid (0.53 g).

ESI-MS : 173 (M + + H).

1 H NMR (CDCl 3) 2.20-4.15 (m, 15H), 9.30-10.20 (m, 1H).

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139

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EDC (1.18 g, 6.15 mmol) was added to a solution agitated acid N-Boc-piperazine-acetic  (1.00 g, 4.10 mmol), 2,6-dimethylmorpholine (605 µl, 4.92 mmol), 3-hydroxybenzotriazole (0.836 g, 6.15 mmol), and diisopropylethylamine (2.14 ml, 12.31 mmol) in DCM (30 ml) at room temperature under nitrogen atmosphere. After stir for 16 h the reaction was quenched by the addition of water (20 ml). The phases were separated and the organic phase was washed with saturated brine (20 ml), dried and evaporated to dryness at reduced pressure The residue was purified by chromatography on silica column, eluting with 0-10% MeOH / DCM to give compound 40 as a white solid (1.31 g).

ESI-MS : 342 (M + + H).

1 H NMR (CDCl 3) 1.20 (d, 6H), 1.46 (s, 9H), 2.34 (dd, 1H), 2.40-2.55 (m, 4H ), 2.75 (dd, 1H). 3.10 (d, 1H), 3.27 (d, 1H), 3.35-3.60 (m, 6H), 3.94 (d, 1H), 4.40 (d, 1H).

1.0 M HCl in Et 2 O (10 ml, 10.0 was added mmol) to a solution of compound 40 (0.58 g, 1.70 mmol) in DCM (2 ml) After stirring at room temperature for 16 h it was added Conc. HCl (1 ml). After stirring for 2 h the solvents under reduced pressure to give compound 41 in the form of a yellow solid (0.46 g).

ESI-MS : 242 (M + + H).

NMR (CDCl3, δ values) 1.13 (d, 6H), 2.35 (t, 1H), 2.70 (t, 1H), 3.25-3.80 (m, 11H) , 4.20 (d, 1H), 4.30-4.48 (m, 1H), 4.50-4.70 (m, 1H), 10.17 (s, 1H).

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140

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A mixture of acid N-Boc-4-piperidinecarboxylic (2.0 g, 8.72 mmol), thiomorpholine (1.2 g, 11.63 mmol), DMAP (4.3g, 35.2 mmol) and EDC (2.2 g, 11.48 mmol) in dichloromethane (75 ml) is stirred under a nitrogen atmosphere for 16 h. Reaction mixture washed with a 1.0 M aqueous solution of citric acid, solution saturated sodium bicarbonate, organic extracts are separated, dried and evaporated to dryness under pressure reduced The residue was triturated with Et2O to give a solid. white, 42 (2.25 g).

1 H NMR (CDCl 3) 1.44 (s, 9H), 1.55-1.82 (m, 4H), 2.50-2.89 (m, 5H), 2.87 (t, 2H), 3.87-3.97 (m, 4H), 4.04-4.28 (m, 2H).

A solution of 1.0M HCl in Et2O was added (5 ml, 5 mmol) to a solution of compound 42 (0.7 g, 2.2 mol) in DCM (50 ml) and the mixture was stirred for 16 h under an atmosphere of nitrogen. The white precipitate was filtered, washed with Et2O and dried to give compound 43 (0.55 g).

ESI-MS : 215 (M + + H).

1 H NMR (DMSOd 6) 1.73 (m, 4H), 2.43-2.69 (m, 4H), 2.80-3.00 (m, 3H), 3.15 -3.35 (m, 2H), 3.70 (m, 4H), 8.71 (wide s, 1H), 9.09 (wide s, 1H).

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141

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A mix of N-Boc-piperazine (0.71 g, 3.82 mmol), uracil-6-acetic acid (0.5 g, 2.94 mmol), DMAP (1.44 g, 11.79 mmol) and EDC (0.736 g, 3.84 mmol) in dichloromethane (40 ml) it was stirred under a nitrogen atmosphere for 16 h. The reaction mixture was treated with aqueous acid solution. 1.0 M citric (50 ml) to give a white precipitate that was filtered, washed with water, DCM and dried to give compound 44 (0.375 g).

1 H NMR (DMSOd 6) 1.53 (s, 9H), 3.40-3.60 (m, 8H), 3.62 (s, 2H), 5.44 (s, 1H ), 10.81 (wide s, 1H), 11.04 (wide s, 1H).

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4.0 M HCl in dioxane (10 ml, 40 mmol) was added to a solution of compound 44 (0.36 g, 1.06 mmol) in dioxane (30 ml) and the mixture was stirred for 72 h under a nitrogen atmosphere. The white precipitate was filtered, washed with more dioxane and then with Et 2 O and dried to give compound 45 (0.26 g).

ESI-MS : 239 (M + + H).

1 H NMR (DMSOd 6) 3.08-3.33 (m, 4H), 3.65 (s, 1H), 3.80 (m, 4H), 5.45 (s, 1H ), 9.60 (wide s, 2H), 10.82 (wide s, 1H), 11.05 (wide s, 1H).

142

EDC (1.18 g, 6.15 mmol) was added to a solution agitated acid N-Boc-piperazine-acetic  (1.00 g, 4.10 mmol), 8-oxa-3-aza-bike [3.2.1] octane (0.566 g, 4.92 mmol), 3-hydroxy benzotriazole (0.836 g, 6.15 mmol), and diisopropylethylamine (2.14 ml, 12.31 mmol) in DCM (20 ml) at room temperature under nitrogen atmosphere. After after stirring for 16 h the reaction was quenched by the addition of water (20 ml). The phases were separated and the organic phase was washed with saturated brine (20 ml), dried and evaporated to dryness at reduced pressure The residue was purified by chromatography on silica, eluting with 0-10% MeOH / DCM to give the compound 46 in the form of a white solid (0.780 g).

ESI-MS : 340 (M + + H).

1 H NMR (CDCl 3) 1.45 (s, 9H), 1.80-2.00 (m, 4H), 2.30-2.58 (m, 4H), 2.85 -3.04 (m, 2H), 3.25 (d, 1H), 3.30-3.57 (m, 3H), 3.78 (d, 1H), 4.12 (d, 1H), 4.36 (d, 3H).

1.0 M HCl in Et 2 O (10 ml, 10.0 was added mmol) and conc. HCl (0.5 ml) to a solution of compound 46 (0.78 g, 2.30 mmol) in DCM (1.5 ml). After stirring at room temperature for 4 h the solvents were removed under reduced pressure to give compound 47 in the form of a yellow solid foam (0.633 g).

143

A mix of N- (tert-butoxycarbonyl) -4- (tosyloxymethyl) -piperidine (0.5 g, 1.35 mmol), piperazin-2-one (0.298 g, 2.96 mmol), DIPEA (0.525 g, 4.06 mmol) in DMA (20 ml) was stirred at 60 ° C for 16 h under a nitrogen atmosphere. DMA is evaporated under reduced pressure and the residue was partitioned between acid 1.0 M aqueous citrus and DCM. The organic layer was separated, dried and evaporated to dryness. It was purified by column chromatography snapshot on silica eluting with EtOAc-MEOH / EtOAc 20% to give compound 48 as a solid foam (0.25 g).

ESI-MS : 298 (M + + H).

1 H NMR (DMSOd 6) 0.97-1.16 (m, 2H), 1.50 (s, 9H), 1.70-1.88 (m, 3H), 2.29 (d, 2H), 2.73-2.92 (m, 2H), 2.99 (s, 2H), 3.23 (m, 2H), 3.40 (s, 2H), 4.00 and 4.04 (2s, 2H), 7.80 (s, 1H).

4.0 M HCl in dioxane (10 ml, 40 mmol) was added to a solution of compound 48 (0.2 g, 0.67 mmol) in dioxane (40 ml) and the mixture was stirred for 72 h under a nitrogen atmosphere. The dioxane was evaporated under reduced pressure to give a gummy solid. This was stirred with Et2O for 3 h and the white solid resulting was isolated by centrifugation and dried to give the compound 49 (0.156 g).

ESI-MS : 198 (M + + H).

1 H NMR (DMSOd 6) 1.42-1.60 (m, 2H), 2.22-2.35 (m, 3H), 2.97 (t, 2H), 3.18 (d, 2H), 3.36 and 3.40 (2s, 2H), 3.38-4.00 (m, 6H).

144

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A mixture of compound 50 (1.5 g, 4.57 mmol) [see intermediate for example 6.21] and MCPBA (70%) (2.25 g, 9.14 mmol) in DCM (50 ml) was stirred under an atmosphere of nitrogen for 48 h. It was then washed with saturated solution of baking soda (2x50 ml), dried and evaporated to dryness under reduced pressure. The residue was washed with Et2O and dried to give compound 51 (1.65 g) as a white solid.

ESI-MS : 361 (M + + H).

1 H NMR (DMSOd 6) 1.06-1.24 (m, 2H), 1.50 (s, 9H), 1.68-1.80 (m, 2H), 1.90 -2.06 (m, 1H), 2.44 (d, 2H), 2.70-2.92 (m, 2H), 3.18 (m, 2H), 3.30 (m, 2H), 3.90-4.08 (m, 6H).

A solution of 1.0 M HCl in Et2O was added (19.4 ml, 19.4 mmol) to a solution of compound 51 (1.4 g, 3.9 mmol) in DCM (60 ml) and the mixture was stirred for 16 h under atmosphere of nitrogen The white precipitate was filtered, washed with Et 2 O and dried to give compound 52 (0.96 g).

ESI-MS : 261 (M + + H).

1 H NMR (DMSOd 6) 1.40-1.60 (m, 2H), 1.86-2.00 (m, 2H), 2.00-2.20 (m, 1H) , 2.50 (d, 2H), 2.88-3.05 (q, 2H), 3.20 (m, 2H), 3.24-3.40 (m, 2H), 3.56 (m , 2H), 3.97 (m, 4H), 8.95 (wide s, 1H), 9.02 (wide s, 1H).

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145

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A mixture of compound 42 (1 g, 3.18 mmol) [see intermediate for example 6.15] and MCPBA (70%) (1.65 g, 6.7 mmol) in DCM (75 ml) was stirred under an atmosphere of nitrogen for 72 h. It was then washed with saturated solution of baking soda (2x50 ml), dried and evaporated to dryness under reduced pressure. The residue was washed with Et2O and dried to give compound 53 (1 g) as a white solid.

ESI-MS : 369 (M + + Na).

1 H NMR (DMSOd 6) 1.29-1.52 (m, 2H), 1.45 (s, 9H), 1.55-1.72 (m, 2H), 2.64 -2.96 (m, 3H), 3.00-3.28 (m, 4H), 3.72-4.00 (m, 6H).

A solution of 1.0 M HCl in Et2O was added (10 ml, 10 mmol) to a solution of compound 53 (1 g, 2.9 mmol) in DCM (80 ml) and the mixture was stirred for 16 h under an atmosphere of nitrogen. The white precipitate was filtered, washed with Et2O and dried to give compound 54 (0.65 g).

ESI-MS : 247 (M + + H).

1 H NMR (DMSOd 6) 1.75-2.00 (m, 4H), 2.91-3.45 (m, 9H), 3.91 (m, 4H), 8.80 (wide s, 1H), 9.10 (wide s, 1H).

146

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A mixture of acid N-Boc-4-piperidine-acetic (2.0 g, 8.2 mmol), thiomorpholine (1 g, 9.7 mmol), DMAP (4.0 g, 32.8 mmol) and EDC (2.0 g, 10.4 mmol) in dichloromethane (80 ml) was stirred in a nitrogen atmosphere for 16 h. The reaction mixture is washed with a 1.0 M aqueous solution of citric acid (2x50 ml), saturated sodium bicarbonate solution, organic extracts separated, dried and evaporated to dryness under pressure reduced The residue was purified by column chromatography. snapshot on silica, eluting with 50-80% EtOAc / iso-hexane to give compound 50 (2.1 g) in the form of a white solid.

1 H NMR (CDCl 3) 1.03-1.22 (m, 2H), 1.46 (s, 9H), 1.67-1.80 (m, 2H), 1.90 -2.05 (m, 1H), 2.22 (d, 2H), 2.58-2.64 (m, 4H), 2.74 (t, 2H), 3.75 (t, 2H), 3.90 (t, 2H), 4.00-4.20 (m, 2H).

A solution of 1.0 M HCl in Et2O was added (10 ml, 10 mmol) to a solution of compound 50 (0.5 g, 1.5 mmol) in DCM (30 ml) and the mixture was stirred for 16 h under an atmosphere of nitrogen. The white precipitate was filtered, washed with Et2O and dried to give compound 55 (0.33 g).

ESI-MS : 229 (M + + H).

1 H NMR (DMSOd 6) 1.40-1.60 (m, 2H), 1.84-2.00 (m, 2H), 2.00-2.20 (m, 1H) , 2.40 (d, 2H), 2.55-2.68 (m, 2H), 2.68-2.78 (m, 2H), 2.82-3.04 (q, 2H), 3 , 20-3.40 (m, 2H), 3.80 (m, 4H), 8.97 (wide s, 1H), 9.15 (wide s, 1H).

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147

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A mixture of acid N-Boc-4-piperidine-acetic (1.0 g, 4.1 mmol), pyrrolidine (0.38 g, 5.3 mmol), DMAP (2.0 g, 16.4 mmol) and EDC (1.0 g, 5.2 mmol) in dichloromethane (60 ml) was stirred in a nitrogen atmosphere for 16 h. Reaction mixture washed with a 1.0 M aqueous citric acid solution (2x50 ml), saturated sodium bicarbonate solution, organic extracts separated, dried and evaporated to dryness under pressure reduced The residue was triturated and washed with Et2O to give the compound 56 (1.15 g).

1 H NMR (CDCl 3) 1.04-1.21 (m, 2H), 1.45 (s, 9H), 1.68-1.79 (m, 2H), 1.80 -2.13 (m, 5H), 2.18 (d, 2H), 2.72 (t, 2H), 3.40 (t, 2H), 3.46 (t, 2H), 3.98- 4.20 (m, 2H).

A solution of 1.0 M HCl in Et2O was added (20 ml, 20 mmol) to a solution of compound 56 (1 g, 3.6 mmol) in DCM (50 ml) and the mixture was stirred for 16 h under an atmosphere of nitrogen. The solvent was decanted and the gummy solid was washed with Et 2 O and then stirred with more Et 2 O for 18 h. He precipitate was filtered and dried to give compound 57 (0.7 g) in Shape of a white solid.

ESI-MS : 197 (M + + H).

1 H NMR (DMSOd 6) 1.40-1.60 (m, 2H), 1.80-2.02 (m, 6H), 2.02-2.20 (m, 1H) , 2.30 (d, 2H), 2.94 (q, 2H), 3.20-3.32 (m, 2H), 3.37 (t, 2H), 3.48 (t, 2H), 9.00 (wide s, 1H), 9.20 (wide s, 1H).

148

A mixture of acid N-Boc-piperazine-acetic (0.5 g, 2.05 mmol), piperazin-2-one (0.3 g, 3.075 mmol), DMAP (1.25 g, 10.23 mmol) and EDC (0.51 g, 2.7 mmol) in dichloromethane (40 ml) was stirred under an atmosphere of nitrogen for 16 h. The reaction mixture was washed with a 1.0 M aqueous citric acid solution and organic extracts are separated, dried and evaporated to dryness under pressure reduced The residue was purified by column chromatography. snapshot on silica eluting with EtOAc-MeOH / EtOAc 20% to give compound 58 as a solid foam (0.38 g).

ESI-MS : 327 (M + + H).

1 H NMR (DMSOd 6) 1.50 (s, 9H), 2.48 (t, 4H), 3.20-3.48 (m, 8H), 3.70 and 3.80 (2t, 2H), 4.02 and 4.25 (2s, 2H), 8.12 (s, 1H).

4.0 M HCl in dioxane (10 ml, 40 mmol) was added to a solution of compound 58 (0.34 g, 0.094 mmol) in dioxane (50 ml) and the mixture was stirred for 16 h under a nitrogen atmosphere. The dioxane was evaporated under reduced pressure to give a gummy solid. This was stirred with Et2O for 3 h and the white solid resulting was isolated by centrifugation and dried to give the compound 59 (0.224 g).

ESI-MS : 227 (M + + H).

1 H NMR (DMSOd 6) 3.26-3.80 (m, 12H), 4.10 (d, 2H), 4.57 (s, 1H), 4.64 (s, 1H ), 8.30 (d, 1 H). 10.22 (broad s, 2H), 3.34-3.55.

149

A mix of 1-Boc-piperazine (1.0 g, 5.4 mmol), 6-chloromethyluracil (0.9 g, 5.6 mmol) and carbonate Potassium (1.5 g, 10.9 mmol) in DMA (50 ml) was stirred at temperature ambient for 16 h in a nitrogen atmosphere. DMA is evaporated under reduced pressure and the residue was stirred with water (30 ml) and acidified with 1.0 M aqueous citric acid at pH 6-7. The white solid precipitate was filtered and dried to give compound 60 (1.0 g).

ESI-MS : 311 (M + + H).

1 H NMR (DMSOd 6) 1.38 (s, 9H), 2.35 (t, 4H), 3.18 (s, 2H), 3.24-3.45 (m, 4H ), 5.47 (s, 1H), 10.64 (wide s, 1H), 10.91 (wide s, 1H).

Triethylsilane (1.0 ml, 12 mmol) was added and then TFA (40 ml) to a stirred suspension of compound 60 (0.55 g, 1.8 mmol) in DCM (10 ml), under a nitrogen atmosphere. After stirred at room temperature for 1 h. The TFA and DCM are evaporated under reduced pressure and the residue was washed with Et2O and dried to give compound 61 (0.5 g) as a solid of cream.

ESI-MS : 211 (M + + H).

1 H NMR (DMSOd 6) 2.61 (t, 4H), 3.10 (m, 4H), 3.20 (s, 2H), 5.50 (s, 1H), 8, 60 (wide s, 2H), 10.65 (wide s, 1H), 10.94 (wide s, 1H).

150

Glacial acetic acid (230 was added dropwise µL, 4.02 mmol) to a stirred solution of N-Boc-3-pyrrolidinone  (0.3 g; 1.62 mmol), hydrochloride 3-methylamino-tetrahydrothiophene-1-dioxide (0.15 g, 0.81 mmol), sodium cyanoborohydride (0.102 g, 1.62 mmol), and molecular sieves of 3A (0.3 g) in MeOH (3 ml) at temperature atmosphere in nitrogen atmosphere. After stirring for 16 h the reaction mixture was filtered through a pad of Celite and the filtrate was evaporated to dryness under reduced pressure. The residue was partitioned between DCM (30 ml) and saturated solution of NaHCO 3 (20 ml), the organic phases were separated and washed more with saturated brine (20 ml), dried and evaporated until dryness. The residue was treated by silica chromatography, eluting with 80% EtOAc / DCM and then 2-5% MeOH / DCM to give compound 62 as a white solid (0.16 g).

ESI-MS : 319 (M + + H).

1 H NMR (CDCl 3) 1.47 (s, 9H), 1.70-1.90 (m, 1H), 1.95-2.10 (m, 1H), 2.12 -2.40 (m, 5H), 2.90-3.35 (m, 7H), 3.40-3.73 (m, 3H).

1.0 M HCl in Et2O (2.5 ml, 2.5) was added mmol) and conc. HCl (0.5 ml) to a solution of compound 62 (0.16 g, 0.50 mmol) in DCM (3 ml). After stirring at room temperature for 3 h the solvents were evaporated under reduced pressure to give compound 63 as a pale yellow solid (0.128 g).

ESI-MS : 219 (M + + H).

1 H NMR (CDCl 3) 2.10-2.40 (m, 17H), 9.73 (s, 1H).

151

Glacial acetic acid was added dropwise (1.54 ml, 26.9 mmol) to a stirred solution of N-Boc-piperazine (1.0 g, 5.38 mmol), tetrahydro-thiophene-3-one (919 µL, 10.76 mmol), sodium cyanoborohydride (0.677 g, 10.75 mmol) and molecular sieves of 3A (2.0 g) in MeOH (20 ml) at room temperature under nitrogen atmosphere. After stirring for 16 h the reaction mixture was filtered through a Celite pad and the filtrate was evaporated to dryness at reduced pressure The residue was partitioned between DCM (50 ml) and saturated NaHCO3 solution (30 ml), the organic phases are separated and washed more with saturated brine (30 ml), dried and evaporated to dryness. The residue was purified by column chromatography on silica, eluting with EtOAc / DCM at 10-40% to give compound 64 in the form of a white solid (0.74 g).

ESI-MS : 273 (M + + H).

1 H NMR (CDCl 3) 1.45 (s, 9H), 1.75-1.90 (m, 1H), 2.20-2.32 (m, 1H), 2.40 -2.60 (m, 4H), 2.65-2.79 (m, 1H), 2.80-3.00 (m, 4H), 3.34-3.55 (m, 4H).

1.0 M HCl in Et 2 O (6.8 ml, 6.8) was added mmol) and conc. HCl (0.5 ml) to a solution of compound 64 (0.37 g, 1.36 mmol) in DCM (2 ml). After stirring at room temperature for 3 h the solvents were evaporated to give compound 65 in the form of a yellow solid (0.283 g).

ESI-MS : 173 (M + + H).

1 H NMR (CDCl 3) 2.00-2.25 (m, 2H), 2.75-4.00 (m, 13H), 9.65 (broad s, 1H).

152

A mixture of hydrochloride dihydrate acid N-Boc-4-piperazine-acetic (0.4 g, 1.26 mmol), N-methyl-2-piperazinone  (0.194 g, 1.7 mmol), DMAP (1.0 g, 8.2 mmol) and EDC (0.4 g, 2.1 mmol) in dichloromethane (60 ml) it was stirred under a nitrogen atmosphere for 16 h. The reaction mixture was washed with an aqueous solution. 1.0 M citric acid (2x50 ml), saturated bicarbonate solution of sodium, the organic extracts were separated, dried and dried. evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica, eluting with MeOH / EtOAc at 10-20% to give compound 66 in the form of a solid foam (0.3 g).

ESI-MS : 341 (M + + H).

1 H NMR (DMSOd 6) 1.50 (s, 9H), 2.48 (m, 4H), 2.97 (s, 3H), 3.22-3.56 (m, 8H ), 3.78 and 3.90 (2t, 2H), 4.09 and 4.29 (2s, 2H).

A solution of 1.0M HCl in Et2O was added (7.6 ml, 7.6 mmol) to a solution of compound 66 (0.26 g, 0.76 mmol) in DCM (50 ml) and the mixture was stirred for 16 h under atmosphere of nitrogen The precipitate was filtered, washed with Et2O and was dried to give compound 67 (0.145 g) as a solid White.

ESI-MS : 241 (M + + H).

1 H NMR (DMSOd 6) 3.00 (s, 3H), 3.36-3.89 (m, 12H), 4.15 (s, 2H), 4.54 and 4.62 (2s, 2H), 10.08-10.25 (wide s v., 2H).

153

Methyl bromoacetate (3.06 g, 20.0 was added mmol) to a stirred solution of 4-Boc-2-methylpiperazine (2.0 g, 10.0 mmol), sodium iodide (0.1 g) and N, N-diisopropylethylamine (3.48 ml, 20 mmol) in DCM (50 ml) at room temperature under nitrogen atmosphere. After stir for 16 h the reaction mixture was washed with water (30 ml), brine (30 ml), dried and evaporated to dryness under pressure reduced The residue was purified by column chromatography on silica, eluting with 0-8% MeOH / DCM to give the compound 68 in the form of a yellow oil (2.7 g).

ESI-MS : 273 (M + + H).

1 H NMR (CDCl 3) 1.05 (d, 3H), 1.47 (s, 9H), 2.50-2.85 (m, 4H), 3.03-3.13 (m, 1H), 3.34 (d, 1H), 3.44 (d, 1H), 3.70 (s, 3H), 3.71-3.82 (m, 2H).

2.0 M NaOH (25 ml, 49.6 mmol) was added to a solution of compound 68 (2.7 g, 9.9 mmol) in THF (150 ml). After stirring at room temperature for 72 h the mixture of reaction was adjusted to pH 7 with 2N HCl and the solvents The residue was partitioned between water and EtOAc, the phases organic were separated, dried and evaporated to dryness to give compound 69 as a yellow solid (2.56 g).

ESI-MS : 259 (M + + H).

1 H NMR (CDCl 3) 0.93 (d, 3H), 1.35 (s, 9H), 2.40-2.80 (m, 4H), 2.86-3.02 (m, 1H), 3.15 (d, 1H), 3.25 (d, 1H), 3.50-3.70 (m, 2H).

A mixture of compound 69 (1.28 g, 5.0 mmol), pyrrolidine (829 µL, 9.9 mmol), HOBt (1.0 g, 7.4 mmol) and EDC (1.7 g, 8.9 mmol) in DMF (30 ml) was stirred under an atmosphere of nitrogen for 16 h. The reaction mixture was evaporated under pressure. reduced and the residue was partitioned between DCM (50 ml) and water (50 ml). The organic phase was washed with brine (20 ml), dried and evaporated until dry. The residue was purified by column chromatography. on silica, eluting with 0-5% MeOH / DCM to give the compound 70 in the form of a yellow oil (0.904 g).

ESI-MS : 312 (M + + H).

1 H NMR (CDCl 3) 1.05 (d, 3H), 1.45 (s, 9H), 1.75-2.02 (m, 5H), 2.38-2.50 (m, 1H), 2.52-2.66 (m, 1H), 2.70-2.80 (m, 2H), 3.02 (d, 1H), 3.09-3.20 (m , 1H), 3.37-3.60 (m, 5H), 3.62-3.80 (m, 1H).

10 N HCl (0.9 ml, 29 mmol) was added to a solution of compound 70 (0.9 g, 2.9 mmol) in DCM (3 ml) and Et 2 O (10 ml) and the mixture was stirred for 16 h at temperature ambient. The solvents evaporated and distilled more forming the azeotrope with toluene before crushing with MeOH / Et2O to give compound 71 as a solid white (0.42 g).

ESI-MS : 212 (M + + H).

1 H NMR (DMSOd 6) 1.00-1.35 (m, 3H), 1.68-1.97 (m, 4H), 2.80-3.80 (m, 13H) .

154

A mixture of compound 69 (1.28 g, 5.0 mmol), morpholine (872 µL, 9.9 mmol), DIPEA (2.58 g, 20 mmol), HOBt (1.0 g, 7.4 mmol) and EDC (1.7 g, 8.9 mmol) in DMF (30 ml) was stirred in a nitrogen atmosphere for 16 h. The reaction mixture is evaporated and the residue was partitioned between DCM (50 ml) and water (50 ml). The organic phase was washed with brine (20 ml), dried and evaporated until dry under reduced pressure. The residue was purified by column chromatography on silica, eluting with MeOH / DCM at 0-5% to give compound 72 as an oil yellow (1.28 g).

ESI-MS : 328.2 (M + + H).

1 H NMR (CDCl 3) 1.05 (d, 3H), 1.48 (s, 9H), 2.30-2.40 (m, 1H), 2.41-2.55 (m, 1H), 2.70-2.80 (m, 1H), 2.95-3.07 (m, 1H), 3.10-3.20 (m, 1H), 3.40-3 , 83 (m, 12H).

10 N HCl (0.6 ml, 20 mmol) was added to a solution of compound 72 (1.28 g, 3.9 mmol) in DCM (3 ml) and Et 2 O (10 ml) and the mixture was stirred for 16 h at temperature ambient. The solvents evaporated and distilled more forming the azeotrope with toluene before crushing with MeOH / Et2O to give compound 73 as a solid white (0.77 g).

ESI-MS : 228 (M + + H).

1 H NMR (DMSOd 6) 1.20-1.44 (m, 3H), 3.20-3.75 (m, 14H), 3.83-4.03 (m, 1H) , 4.30-4.60 (m, 2H).

155

Bromo-methyl acetate (771 mg, 5.0 mmol) was added to a stirred solution of (1S, 4S) - (-) - 2,5-diazabicyclo [2.2.1] -heptane-2-carboxylic acid tert - butyl (0.5 g, 2.5 mmol), sodium iodide (0.1 g) and N, N-diisopropylethylamine (1.32 ml, 7.6 mmol) in DCM (10 ml) at room temperature under nitrogen atmosphere . After stirring for 16 h the reaction mixture was washed with water (30 ml), brine (30 ml), dried and evaporated to dryness. The residue was purified by column chromatography on silica, eluting with 0-5% MeOH / DCM to give compound 74 as a yellow oil (0.25 g).

ESI-MS : 271 (M + + H).

2.0 M NaOH (2.3 ml, 4.6 mmol) was added to a solution of compound 74 (0.25 g, 0.9 mmol) in THF (3 ml). After stirring at room temperature for 24 h, the reaction mixture it was adjusted to pH 7 with 2N HCl and the solvents were evaporated. He residue was partitioned between water and EtOAc, the organic phases were separated, dried and evaporated to dryness to give the compound 75 in the form of a yellow solid (0.238 g).

ESI-MS : 257 (M + + H).

A mixture of compound 75 (0.119 g, 0.5 mmol), morpholine (82 µL, 0.9 mmol), HOBt (0.095 g, 0.7 mmol), DIPEA (0.26 g, 2.0 mmol) and EDC (0.161 g, 0.8 mmol) in DMF (5 ml) was stirred in a nitrogen atmosphere for 16 h. Reaction mixture it was evaporated and the residue was partitioned between DCM (20 ml) and water (10 ml) The organic phase was washed with brine (10 ml), dried and dried. evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica, eluting with MeOH / DCM at 0-5% to give compound 76 as an oil yellow (0.03 g).

ESI-MS : 326 (M + + H).

1 H NMR (CDCl 3) 1.48 (s, 9H), 1.64-1.97 (m, 2H), 2.54-2.80 (m, 1H), 2.87 -3.10 (m, 1H), 3.12-3.28 (m, 1H), 3.30-3.80 (m, 12H), 4.30 (d, 1H).

2N HCl in Et2O (460 µL, 0.9 was added mmol) to a solution of compound 76 (0.03 g, 0.09 mmol) in DCM (0.5 ml) and stirred for 16 h at room temperature. The solvents were evaporated to give compound 77 as a yellow glass (0.024 g).

ESI-MS : 226 (M + + H).

Example 7 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] 4- [1-oxo-2-methyl-2- {4- (1 , 1-dioxidotetrahydro-3-thienyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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156

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Was added 1- (tetrahydro-1,1-dioxide-3-thienyl) -piperazine (0.084 g, 0.41 mmol) to a stirred solution of compound 78 (0.1 g, 0.21 mmol), catalytic NaI and diisopropylethylamine (180 µl, 1.04 mmol) in DMF (3 ml). After stirring for 16 h at 90 ° C in atmosphere of N2, the reaction mixture was evaporated to dryness at reduced pressure The residue was partitioned between DCM (10 ml) and water (5 ml), the organic extracts were separated, washed with brine (5 ml), dried and evaporated to dryness. He crude product was purified by silica chromatography, eluting with 0-4% MeOH / DCM to give the compound of Example 7 in the form of a yellow solid foam (0.068 g).

Yield: 51%

ESI-MS : 651 (M + + H).

1 H NMR (DMSOd 6) 1.18 (d, 3H), 1.20-1.40 (m, 4H), 1.45-1.80 (m, 10H), 1.98 -2.13 (m, 1H), 2.25-2.65 (m, 15H), 2.85-3.10 (m, 2H), 3.11-3.30 (m, 3H), 3 , 70-3.80 (m, 1H), 4.00-5.00 (m, 2H), 7.06 (s, 1H), 7.12 (s, 2H), 7.20 (s, 1H ), 8.98 (s, 1 H)

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157

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Compound 78 was prepared in a similar manner. to the synthesis of compound 31 using chloride 2-chloropropionyl instead of chloroacetyl and DCE instead of DCM (see example 6).

ESI-MS : 482.95, 484.91 (M + + H).

1 H NMR (DMSOd 6) 1.2-1.6 (m, 8H), 1.50 and 1.52 (2s, 6H), 1.54 (d, 3H), 2.32 (s, 6H), 4.12-4.40 (m, 2H), 5.00 (q, 1H), 7.08 (s, 1H), 7.10 (s, 1H), 7.20 ( s, 2H), 12.40 (wide s, 1H).

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Examples 7.1-7.2

Following a procedure similar to that described In Example 7, the compounds of Table 7 were prepared.

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TABLE 7

158

For the synthesis of intermediate products of side chains refer to the reader to example 6.3 for Example 7.1 and Example 6.13 for Example 7.2.

Example 8 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [1-oxo-3- {4- (1,1- dioxidotetrahydro-3-thienyl) piperazin-1-yl} propyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

159

Example 8 was prepared using the method of example 6 and 79 instead of 31.

ESI-MS : 651 (M + + H).

Starting material 79 was prepared from of compound 32 using the procedure described to prepare the compound 31 and 3-chloropropionyl chloride instead of chloroacetyl chloride.

ESI-MS : 482.92, 484.90 (M + + H).

1 H NMR (DMSOd 6) 1.2-1.6 (m, 8H), 1.57 (s, 6H), 2.33 (s, 6H), 3.05 (t, 2H ), 3.82 (t, 2H), 4.02-4.39 (m, 2H), 7.06 (s, 1H), 7.09 (s, 1H), 7.20 (s, 2H) , 12.21 (wide s, 1H).

Examples 8.1-8.5

Following a procedure similar to that described In Example 8, the compounds of Table 8 were prepared.

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TABLE 8

160

161

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Example 9 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- (1-oxo-2,2-di-methyl-3- {4- (pyrrolidin-1-ylcarbonylmethyl) piperazin-1-yl} propyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

162

The compound of example 9 was prepared using the method of example 6 and 80 instead of 31 and heating for 72 h.

ESI-MS : 672 (M + + H).

1 H NMR (CDCl 3) 1.08-1.75 (m, 8H), 1.18 (s, 6H), 1.73 (s, 6H), 1.75-2.00 (m, 4H), 2.32 (s, 6H), 2.20-2.75 (m, 12H), 3.05 (s, 2H), 3.38-3.55 (m, 2H), 4.10-4.80 (m, 2H), 6.92 (s, 1H), 6.96 (s, 1H), 7.09 (s, 2H), 8.54 (s, 1H).

The starting material 80 was prepared from of compound 32 using the procedure described to prepare the compound 31 and 3-chloropivaloyl chloride instead of chloroacetyl chloride.

ESI-MS : 511 (M + + H).

1 H NMR (DMSOd 6) 1.20 (s, 6H), 1.20-1.60 (m, 8H), 1.52 (s, 6H), 2.27 (s, 6H ), 3.80 (s, 2H), 4.04, 4.40 (m, 2H), 6.96 (s, 1H), 7.04 (s, 2H), 7.26 (s, 1H) , 12.10 (wide s, 1H).

The compound of Example 9.1 was synthesized by procedure used to prepare the compound of example 9 and the suitable starting material:

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163

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ESI-MS : 688 (M + + H).

1 H NMR (DMSO d 6) 1.19-1.65 (m, 7H), 1.51 (s, 6H), 1.80-2.00 (m, 1H), 2, 08-2.60 (m, 8H), 2.24 (s, 6H), 2.29 (s, 6H), 2.60-2.80 (m, 3H), 2.71 and 2.89 ( 2s, 2H), 2.80-2.95 (m, 1H), 2.95-3.40 (m, 6H), 4.09-4.45 (m, 2H), 7.04 (s, 1H), 7.08 (s, 1H), 7.17 (s, 2H), 12.13 (wide s, 1H).

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Example 10 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (pyrrolidin-1-ylcarbonylmethyl) piperazin- 1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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164

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A mixture of compound 29 (0.182 g; 0.4 mmol), N- (pyrrolidinocarbonylmethyl) -piperazine (0.095 g, 0.48 mmol), NaI (0.072 g; 0.48 mmol) and K 2 CO 3 (0.067 g; 0.48 mmol) in acetonitrile (4 ml) was heated at 80 ° C under an atmosphere of Argon for 8 hours. The crude mixture was evaporated and purified by flash chromatography eluting with a gradient of NH3 3.5 N in MeOH / 2-5% methylene chloride to give after trituration in ether / pentane the compound of the example 10 in the form of a solid.

Yield: 42%

1 H NMR (CDCl 3): 1.15-1.4 (m, 6H); 1.45-1.75 (m, 6H); 1.59 (s, 6H); 1.8-2 (m, 4H); 2.32 (s, 6H); 2.45-2.75 (m, 6H); 2.9-3 (m, 2H); 3.1 (s, 2H); 3.44-3.5 (m, 4H); 4-4.2 (m, width, 1H); 4.6-4.8 (m, width, 1H); 6.72 (s, 1 H); 6.92 (s, 1 H); 7.04 (s, 2H); 8.13 (s, 1 H).

EM-ESI: 616 [M + H] +

Example 11 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (2,4-dioxo-1, 2,3,4-tetrahydropyrimidin-6-ylmethyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

165

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A mixture of compound 18 (0.222 g; 0.5 mmol), 6-chloromethyluracil (0.088 g; 0.55 mmol), K 2 CO 3 (0.076 g; 0.55 mmol) and NaI (0.082 g; 0.55 mmol) in Acetonitrile (5 ml) was heated at 85 ° C under argon during 4 hours. The mixture was purified by flash chromatography. eluting with a gradient of MeOH / CH2Cl2 at 5-10% to give the compound of example 11 as of a solid.

Yield: 63%

1 H NMR (CDCl 3): 1.2-1.4 (m, 4H); 1.6 (s, 6H); 1.4-1.8 (m, 4H); 2.34 (s, 6H); 2.4-2.7 (m, 10H); 2.85-2.95 (m, 2H); 3.3 (s, 2H); 4-4.2 (m, width, 1H); 4.6-4.8 (m, width, 1H); 5.53 (s, 1 H); 6.72 (s, 1 H); 6.93 (s, 1 H); 7.04 (s, 2H); 8.05-8.2 (m, 2H).

EM-ESI: 629 [M + H] +

The starting material was prepared as follow:

166

A mixture of compound 29 (12.4 g; 0.027 mol), N- (tert-butoxycarbonyl) piperazine (10.15 g; 0.054 mol), K 2 CO 3 (7.52 g; 0.054 mol) in acetonitrile (120 ml) was heated at 85 ° C under argon for 3 hours. The mixture was evaporated and purified by flash chromatography, eluting with a gradient of ethyl acetate / petroleum ether 50-100 to give compound 81.

Yield: 94%

1 H NMR (CDCl 3): 1.15-1.4 (m, 4H); 1.45-1.8 (m, 4H); 1.44 (s, 9H); 1.6 (s, 6H); 2.33 (s, 6H); 2.35-2.5 (m, 4H); 2.6-2.7 (m, 2H); 2.9-3 (m, 2H); 3.4-3.5 (m, 4H); 4.0-4.2 (m, width, 1H); 4.6-4.8 (m, width, 1H); 6.71 (s, 1 H); 6.93 (s, 1 H); 7.04 (s, 2H); 8.13 (s, 1 H).

To a solution of compound 81 (15.32 g; 0.025 mol) in methylene chloride (250 ml) TFA (95 ml) was added at 0 ° C. After stirring at room temperature for 1 hour, the mixture it was evaporated, treated with 3.5 N NH 3 in MeOH (100 ml) and purified by flash chromatography eluting with a gradient of 3.5 N NH 3 in 5-8% MeOH / CH 2 Cl 2 to give after compound trituration with ether 18 in the form  of a solid.

Yield: 95%

1 H NMR (CDCl 3): 1.15-1.4 (m, 4H); 1.45-1.75 (m, 4H); 1.6 (s, 6H); 2.33 (s, 6H); 2.5 (m, 4H); 2.6-2.7 (m, 2H); 2.85-3 (m, 6H); 4.0-4.2 (m, width, 1H); 4.6-4.8 (m, width, 1H); 6.72 (s, 1 H); 6.92 (s, 1 H); 7.05 (s, 2H); 8.15 (s, 1 H).

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Examples 11.1-11.7

Following a procedure similar to that described in example 11, the compounds of table 11 were prepared.

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TABLE 11

167

168

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Example 12 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (morpholinocarbonyl) piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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169

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Chloride was added 4-morpholinocarbonyl (0.058 g; 0.367 mmol) in atmosphere of argon at 0 ° C, to a suspension of compound 18 (0.185 g; 0.367 mmol) and triethylamine (0.054 ml; 0.385 mmol) in acetonitrile (4 ml). The mixture was stirred at room temperature for 3 hours. After evaporation to dryness, the residue was purified by instant chromatography, eluting with a gradient of 5-7% NH3 3.5 N in MeOH / methylene chloride to give after trituration in ether the compound of the example 12 in the form of a solid.

Yield: 60%

1 H NMR (CDCl 3): 1.15-1.4 (m, 4H); 1.6 (s, 6H); 2.45-2.8 (m, 4H); 2.33 (s, 6H); 2.47-2.50 (m, 4H); 2.6-2.7 (m, 2H); 2.9-3 (m, 2H); 3.15-3.4 (m, 8H), 3.6-3.7 (m, 4H); 4-4.2 (m, width, 1 HOUR); 4.6-4.8 (m, width, 1H); 6.7 (s, 1 H); 6.93 (s, 1 HOUR); 7.03 (s, 2H); 8.13 (s, 1 H).

EM-ESI: 618 [M + H] +

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Examples 12.1-12.7

Following a procedure similar to that described In Example 12, the compounds of Table 12 were prepared.

TABLE 12

170

171

Example 13 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {N, N-dimethylaminocarbonylmethyl} piperazin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

172

The compound of example 13 was prepared following a procedure similar to that described in example 11.

Yield: 89%

1 H NMR (CDCl 3): 1.2-1.4 (m, 4H); 1.63 (s, 6H); 1.5-1.8 (m, 4H); 2.36 (s, 6H); 2.63 (s, 6H); 2.5-2.7 (m, 10H); 2.9-3 (m, 2H); 3.18 (s, 2 H); 4-4.2 (m, width, 1H); 4.65-4.85 (m, 1 H); 6.75 (s, 1 H); 6.95 (s, 1 H); 7.08 (s, 2H); 8.52 (s, 1 H). MS-BSI: 590 [M + H] +

Example 14 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (N-isopropylaminocarbonylmethyl) piperazin-1- il) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

173

The compound of example 14 was prepared following a procedure similar to that described in example 10.

Yield: 68%

1 H NMR (CDCl 3): 1.15 (d, 6H); 1.2-1.4 (m, 4H); 1.6 (s, 6H); 1.5-1.8 (m, 4H); 2.3 (s, 6H); 2.45-2.7 (m, 10H); 2.85-3 (m, 2H); 2.95 (s, 2 H); 4-4.20 (m, width, 2H); 4.6-4.8 (m, width, 1H); 6.71 (s, 1 H); 6.93 (m, 2H); 7.04 (s, 2H); 8.12 (s, 1 H).

EM-ESI: 604 [M + H] +

Example 15 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {tetrahydrofuran-2-ylcarbonyl} piperazin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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174

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The compound of example 15 was prepared following a procedure similar to that described in example 10.

Yield: 73%

1 H NMR (CDCl 3): 1.2-1.4 (m, 4H); 1.5-1.7 (m, 4H); 1.6 (s, 6H); 1.8-2.3 (m, 4H); 2.35 (s, 6H); 2.4-2.55 (m, 4H); 2.65-2.75 (m, 2H); 2.9-3 (m, 2H); 3.5-3.7 (m, 4H); 3.8-4 (m, 2H); 4-4.2 (m, width, 1H); 4.6 (m, 1 H); 4.6-4.8 (m, width, 1H); 6.73 (s, 1 H); 6.95 (s, 1 H); 7.06 (s, 2H); 8.16 (s, 1 H).

EM-ESI: 603 [M + H] +

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Example 16 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {hydroxyethoxyethyl} piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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175

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The compound of example 16 was prepared following a procedure similar to that described in example 10.

Yield: 34%

1 H NMR (DMSOd 6): 1.2-1.4 (m, 4H); 1.5-1.65 (m, 4H); 1.55 (s, 6H); 2.34 (s, 6H); 2.4-2.7 (m, 12H); 2.9 (wide s, 2H); 3.48 (t, 2H); 3.56 (t, 2H); 3.58 (broad s, 2H); 4.1 (s wide, 1H); 4.6 (broad s, 1H); 6.73 (broad s, 1H); 6.9 (s, 1 H); 7.08 (s, 2H); 11-12 (wide s, 1H).

EM-ESI: 593 [M + H] +

Example 17 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (1,3-dimethyl-2, 4-dioxo-1,2,3,4-tetrahydropyrimidin-6-ylmethyl) piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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176

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The compound of example 17 was prepared following a procedure similar to that described in example 11.

Yield: 54%

1 H NMR (CDCl 3) (δ ppm) 1.22-1.44 (m, 4H); 1.52-1.79 (m, 10H); 2.34 (s, 6H); 2.44-2.73 (m, 8H); 2.93 (m, 2H); 3.26 (s, 2H); 3.34 (s, 3 H); 3.42 (s, 3 H); 4.10 (broad s, 1H); 5.75 (broad s, 1H); 5.73 (s, 1 H): 6.73 (s, 1 H); 6.94 (s, 1 H); 7.03 (s, 2H); 8.12 (s, 1 H).

EM-ESI: 657 [M + H] +

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Example 18 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {piperidin-1-ylcarbonylmethyl} piperazin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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177

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The compound of example 18 was prepared following a procedure similar to that described in example 11.

Yield: 50%

1 H NMR (CDCl 3): 1.2-1.4 (m, 6H); 1.6 (s, 6H); 1.5-1.8 (m, 10H); 2.35 (s, 6H); 2.45-2.7 (m, 8H); 2.9-3 (m, 2H); 3.17 (s, 2H); 3.45-3.6 (m, 4H); 4.0-4.2 (m, width, 1H); 6.6-6.8 (m, width, 1H); 6.74 (s, 1 H); 6.94 (s, 1 H); 7.06 (s, 2H); 8.11 (s, 1 H).

EM-ESI: 630 [M + H] +

Example 19 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {azetidin-1-ylcarbonylmethyl} piperazin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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178

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The compound of example 19 was prepared following a procedure similar to that described in example 11.

Yield: 50%

1 H NMR (CDCl 3): 1.2-1.4 (m, 6H); 1.45-1.8 (m, 6H); 1.6 (s, 6H); 2.25-2.35 (m, 2H); 2.35 (s, 6H); 2.45-2.7 (m, 6H); 2.9-3 (m, 2H); 3.00 (s, 2H); 4.0-4.1 (m, 2H); 4.0-4.2 (m, width, 1H); 4.2-4.3 (m, 2H); 4.6-4.8 (m, width, 1H); 6.74 (s, 1 H); 6.94 (s, 1 HOUR); 7.06 (s, 2H); 8.15 (1H).

EM-ESI: 602 [M + H] +

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Example 20 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4-pyrid-4-ylpiperidin-1-yl ) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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179

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A mixture of compound 29 (0.222 g; 0.555 mmol), 4- (4-piperidinyl) pyridine (0.090 g, 0.555 mmol), K 2 CO 3 (0.092 g; 0.66 mmol) in acetonitrile (2 ml) was heated at 85 ° C under argon for 2 hours. The Crude mixture was evaporated and purified by flash chromatography. eluting with a gradient of NH3 3.5 N in MeOH / chloride 5-7% methylene to give after crushing in ether / pentane the compound of example 20 in the form of a solid.

Yield: 34%

1 H NMR (CDCl 3): 1.2-1.45 (m, 4H); 1.65 (s, 6H); 1.5-1.8 (m, 4H); 1.8-1.95 (m, 4H); 2.18 (t, 2H); 2.38 (s, 6H); 2.5-2.6 (m, 1 H); 2.7-2.8 (m, 2H); 2.95-3.05 (m, 2H); 3.15-3.25 (m, 2H); 4-4.2 (m, width, 1 HOUR); 4.65-4.85 (m, width, 1H); 6.78 (s, 1 H); 6.98 (s, 1 H); 7.10 (s, 2H); 7.18 (d, 2H); 8.22 (s, 1 H); 8.53 (d, 2H).

EM-ESI: 581 [M + H] +

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Examples 20.1-20.6

Following a procedure similar to that described in example 20, the compounds of table 20 were prepared.

TABLE 20

180

Example 21 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (1,1-dioxidotetrahydrotien-3- il) piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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181

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A mixture of compound 29 (0.28 g; 0.5 mmol), 1- (1,1-dioxo-tetrahydro-1-gamma- (6) -thiophene-3-yl) -piperazine  (0.24 g; 1.0 mmol), DIEA (0.435 ml; 2.5 mmol) and NaI (0.074 g; 0.5 mmol) in DMF (4 ml) was heated at 110 ° C under argon for 24 hours After extracting with ethyl acetate and evaporation, the mixture was purified by flash chromatography, eluting with methylene chloride / NH3 3.5 N in MeOH to give the compound of example 21.

Yield: 27%

1 H NMR (CDCl 3): 1.2-1.4 (m, 4H); 1.5-1.8 (m, 4H); 1.68 (s, 6H); 2.15 (m, 1 H); 2.35 (s, 6H); 2.42 (m, 1 H); 2.5-2.7 (m, 8H); 2.67 (m, 2 H); 2.92 (m, 2H); 3-3.1 (m, 2H); 3.2-3.3 (m, 3H); 4.0-4.2 (m, width, 1H); 4.6-4.8 (m, width, 1H); 6.73 (s, 1 H); 6.95 (s, 1 H); 7.06 (s, 2H); 8.17 (s, 1 HOUR).

EM-ESI: 623 [M + H] +

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Example 22 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (4-methylpiperazin-1-ylcarbonyl) piperidin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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182

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The compound of example 22 was prepared following a procedure similar to that described in example 5. Performance: 71%

1 H NMR (CDCl 3): 1.2-1.4 (m, 6H); 1.45-1.75 (m, 6H); 1.6 (s, 6H); 1.85-2 (m, 2H); 2.0-2.1 (m, 2H); 2.25-2.5 (m, 3H); 2.31 (s, 3 H); 2.37 (s, 6H); 2.6-2.7 (m, 2H); 2.9-3.15 (m, 4H); 3.45-3.7 (m, 4H); 4.0-4.2 (m, width, 1H); 4.6-4.8 (m, width, 1H); 6.74 (s, 1 H); 6.94 (s, 1 H); 7.07 (s, 2H); 8.13 (s, 1 H).

EM-ESI: 630 [M + H] +

Example 23 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (4-acetylpiperazin-1-ylcarbonyl) piperidin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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183

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The compound of example 23 was prepared following a procedure similar to that described in example 5.

Yield: 26%

1 H NMR (CDCl 3): 1.2-1.4 (m, 4H); 1.5-1.8 (m, 6H); 1.62 (s, 6H); 1.85-2.14 (m, 4H); 2.13 (s, 3 H); 2.35 (s, 6H); 2.4-2.5 (m, 1 H); 2.6-2.75 (m, 2H); 2.9-3.15 (m, 4H); 3.4-3.7 (m, 8H); 4.0-4.2 (m, 1 H); 4.6-4.8 (m, 1 H); 6.74 (s, 1 H); 6.95 (s, 1 H); 7.07 (s, 2H); 8.15 (s, 1 H).

EM-ESI: 658 [M + H] +

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Example 24 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [Z- {4 - ((3aR, 6aS) -tetrahydro- 3aH- [1,3] dioxolo [4,5-c] pyrrol-5-ylcarbonyl) piperidin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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184

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The compound of example 24 was prepared following a procedure similar to that described in example 5.

Yield: 26%

1 H NMR (CDCl 3): 1.2-1.4 (m, 4H); 1.5-2.1 (m, 10H); 1.64 (s, 6H); 2.3-2.4 (m, 1 H); 2.35 (s, 6H); 2.65-2.68 (m, 2H); 2.93-2.97 (m, 2H); 3.06-3.08 (m, 2H); 3.35-3.54 (m, 2H); 3.82-4.08 (m, 2H); 4.0-4.2 (m, width, 1H); 4.69-4.70 (m, 3H); 4.98 (d, 2H); 6.74 (s, 1 H); 6.94 (s, 1 H); 7.07 (s, 2H); 8.15 (s, 1 H).

EM-ESI: 645 [M + H] +

Example 25 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (3-pyrid-4-ylazetidin-1-yl ) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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185

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The compound of example 25 was prepared following a procedure similar to that described in example 4.

Yield: 26%

1 H NMR (CDCl 3): 1.1-1.3 (m, 4H); 1.35-1.7 (m, 4H); 1.52 (s, 6H); 2.24 (s, 6H); 2.74-2.8 (m, 4H); 3.05-3.2 (m, 2H); 3.5-3.7 (m, 3H); 3.95-4.15 (m, 1 H); 4.5-4.7 (m, 1M); 6.67 (s, 1 H); 6.84 (s, 1 H); 7.01 (s, 2H); 7.09 (d, 2H); 8.42 (d, 2H); 8.75 (s, 1 H).

ESI-MS: [M + H] +

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Example 26 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {morpholinocarbonylmethyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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186

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A mixture of compound 29 (0.137 g; 0.3 mmol), 4- (4-piperidinylacetyl) -morpholine (0.127 g, 0.51 mmol), K 2 CO 3 (0.121 g; 0.81 mmol) in DMA (3 ml) was heated at 85 ° C under argon for 6 hours. The Crude mixture was evaporated and purified by flash chromatography. eluting with a gradient of NH3 3.5 N in MeOH / chloride 5-7% methylene to give after crushing in ether / pentane the compound of example 26 in the form of a solid.

Yield: 71%

1 H NMR (CDCl 3): 1.2-1.4 (m, 8H); 1.6 (s, 6H); 1.5-1.8 (m, 4H); 1.75-1.85 (m, 2H); 1.8-1.95 (m, width, 1H); 2-2.15 (m, 2H); 2.25-2.26 (m, 2H); 2.35 (s, 6H); 2.6-2.7 (m, 2H); 2.9-3.1 (m, 4H); 4.45-4.55 (m, 2H); 3.6-3.7 (m, 4H); 4-4.2 (m, width, 1H); 4.65-4.85 (m, width, 1H); 6.74 (s, 1 H); 6.94 (s, 1 H); 7.06 (s, 2H); 8.12 (s, 1 HOUR).

EM-ESI: 631 [M + H] +

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Examples 26.1-26.5

Following a procedure similar to that described in example 26, the compounds of table 26 were prepared.

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TABLE 26

187

Example 27 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {tetrahydro-2H-pyran-4- ilcaxbonylamino} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

189

EDC (0.091 g; 0.475 mmol) was added to a stirred solution of compound 82 (0.176 g; 0.317 mmol), HOBT (0.064  g; 0.475 mmol) and acid tetrahydropyran-4-yl-carboxylic (0.11 g; 0.634 mmol) in DMF (3 ml). After stirring for 1 hour, the mixture was evaporated and purified by chromatography instantaneous, eluting with MeOH / methylene chloride 3/97 to give the compound of example 27 in the form of a solid.

Yield: 50%

1 H NMR (CDCl 3): 1.2-1.4 (m, 4H); 1.5-1.85 (m, 6H); 1.62 (s, 6H); 1.9-2 (m, 2H); 2.1-2.4 (m, 7H); 2.35 (s, 6H); 2.65-2.75 (m, 2H); 2.9-3.05 (m, 4H); 3.35-3.45 (m, 2H); 3.75-3.9 (m, 1 H); 4.0-4.1 (m, 2H); 4.0-4.2 (m, width, 1H); 4.65-4.85 (m, width, 1H); 5.5 (d, 1 H); 6.78 (s, 1 H); 6.95 (s, 1 H); 7.05 (s, 2H); 8.14 (s, 1 H).

EM-ESI: 631 [M + H] +

The starting material was prepared as follow:

190

A mixture of compound 29 (0.17 g; 3.7 mmol), 4-N- (tert-butoxycarbonyl) -aminopiperidine (0.972 g, 4.85 mmol), NaI (0.554 g; 4.85 mmol) and K 2 CO 3 (0.67 g; 4.85 mmol) in dimethylacetamide (17 ml) was heated to 85 ° C under argon for 3 hours. The crude mixture evaporated and purified by flash chromatography eluting with a gradient of NH3 3.5 N in MeOH / methylene chloride at 2-4% to give after crushing in pentane compound 83 in the form of a solid.

Yield: 87%

1 H NMR (CDCl 3): 1.2-1.4 (m, 4H); 1.44 (s, 9H); 1.5-1.8 (m, 4H); 1.63 (s, 6H); 1.9-2.1 (m, 2H); 2.10-2.40 (m, 2H); 2.36 (s, 6H); 2.6-2.9 (m, 2H); 2.9-3.2 (m, 2H); 3.48-3.62 (m, 1 H); 4.0-4.2 (m, 1 H); 4.5 (broad s, 1H); 4.6-4.85 (broad s, 1H); 6.81 (broad s, 1H); 6.95 (s, 1 HOUR); 7.05 (s, 2H); 8.25 (wide s, 1H).

A solution of compound 83 (2 g; 0.32 mmol) in dioxane (20 ml), it was treated at 0 ° C with 12 N HCl (5 ml). After 1 hour, the mixture was stirred at room temperature for 3 hours; be evaporated and triturated in ether / pentane to give compound 82 in solid form.

Yield: 100%

1 H NMR (DMSOd 6): 1.2-1.4 (m, 4H); 1.4-1.7 (m, 4H); 1.54 (s, 6H); 2.0 (m, 2H); 2.15 (m, 2H); 2.36 (s, 6H); 3.05-3.35 (m, 6H); 3.60-3.75 (m, 2H); 4.0-4.2 (m, 1 H); 4.3-4.5 (m, 1 HOUR); 6.97 (s, 1 H); 6.99 (s, 1 H); 7.11 (s, 2H); 8.33 (broad s, 2H); 10.8 (broad s, 1H); 11.49 (s, 1 H).

EM-ESI: 519 [M + H] +

Examples 27.1-27.4

Following a procedure similar to that described In Example 27, the compounds of Table 27 were prepared.

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TABLE 27

191

Example 28 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {morpholinocarbonylamino} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

193

Chloroformate was added 4-nitrophenyl (0.111 g; 1.1 mmol) under an atmosphere of argon at 0 ° C, to a solution of compound 82 (0.277 g; 0.5 mmol) and triethylamine; after stirring at room temperature for 1 hour, morpholine (0.052 ml; 0.6 mmol) was added. After 2 hours, the mixture was purified by flash chromatography eluting with a gradient of NH3 3.5 N in MeOH / CH2Cl2 at 2-8% to give after crushing with pentane-ether the compound of example 28 in the form of a solid.

Yield: 38%

1 H NMR (CDCl 3): 1.2-1.8 (m, 10H); 1.61 (s, 6H); 1.95-2.05 (m, 2H); 2.1-2.25 (m, 2H); 2.34 (s, 6H); 2.6-2.7 (m, 2H); 2.9-3 (m, 4H); 3.3-3.4 (m, 4H); 3.65-3.8 (m, 5H); 4.0-4.2 (m, width, 1 HOUR); 4.4 (d, 1 H); 4.6-4.8 (m, width, 1H); 6.8 (s, 1 HOUR); 6.94 (s, 1 H); 7.05 (s, 2H); 8.17 (s, 1 H). ESI-MS: 632 [M + H] +

Examples 28.1-28.3

Following a procedure similar to that described in example 28, the compounds of table 28 were prepared.

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TABLE 28

194

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Example 29 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {N, N-dimethylaminosulfonylamino} piperidin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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195

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A mixture of compound 29 (0.225 g; 0.5 mmol), N, N-dimethyl-N'-4-piperidinyl sulfamide (0.250 g, 0.6 mmol), and K 2 CO 3 (0.083 g; 0.6 mmol) in dimethylacetamide (3 ml) was heated at 85 ° C under argon for 5 hours The crude mixture was evaporated and purified by Instant chromatography eluting with NH3 3.5 95/5 N-MeOH / methylene chloride to give later from the crushing in pentane the compound of example 29 in the form of a solid.

Yield: 50%

1 H NMR (CDCl 3): 1.2-1.45 (m, 4H); 1.5-1.8 (m, 6H); 1.61 (s, 6H); 2.0-2.1 (m, 2H); 2.1-2.2 (m, 2H); 2.34 (s, 6H); 2.6-2.7 (m, 2H); 2.8 (s, 6H); 2.85-2.95 (m, 4H); 3.2-3.3 (m, 1 H); 4.0-4.2 (m, width, 1H); 4.28 (d, 1 H); 4.6-4.8 (m, width, 1H); 6.75 (s, 1 H); 6.93 (s, 1 H); 7.05 (s, 2H); 8.6 (s, 1 H).

EM-ESI: 626 [M + H] +

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Example 30 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {3-oxo-3-morpholinoprop- 1-yl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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196

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A mixture of compound 29 (0.137 g; 0.3 mmol), compound 85 (0.158 g, 0.6 mmol), K 2 CO 3 (1.24 g; 0.9 mmol) in acetonitrile (3 ml) and DMA (2 ml) was heated at 85 ° C for One night in an argon atmosphere. The crude mixture was evaporated and purified by flash chromatography eluting with a gradient of 3.5 N NH3 in 5-7% MeOH / methylene chloride to give after trituration in ether / pentane the compound of Example 30 in the form of a solid.

Yield: 61%

1 H NMR (CDCl 3): 1.2-1.4 (m, 6H); 1.5-1.8 (m, 9H); 1.6 (s, 6H); 1.95-2.05 (m, width, 2H); 2.3-2.4 (m, 2H); 2.35 (s, 6H); 2.6-2.7 (m, 2H); 2.9-3.1 (m, 4H); 3.4-3.5 (m, 2H); 3.6-3.7 (m, 6H); 4.0-4.2 (m, width, 1H); 4.65-4.85 (m, width, 1H); 6.74 (s, 1 H); 6.94 (s, 1 H); 7.06 (s, 2H); 8.14 (s, 1 HOUR).

EM-ESI: 646 [M + H] +

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The starting material was prepared as follow:

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197

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EDC (1.25 g; 6.5 mmol) was added to a solution agitated acid 1-tert-butoxicaxbonyl-4-piperidine-propionic  (1.29 g; 5 mmol), HOBT (0.878 g; 6.5 mmol) and morpholine (0.57 g; 6.5 mmol) in methylene chloride (15 ml). After stirring for 18 hours, the mixture was evaporated and purified by chromatography instantaneous, eluting with MeOH / methylene chloride 3/97 to give the compound 84 in the form of a solid.

Yield: 100%

1 H NMR (CDCl 3): 1.1-1.3 (m, 2H); 1.45 (s, 9H); 1.4-1.5 (m, 1 H); 1.55-1.75 (m, 4H); 2.33 (t, 2H); 2.6-2.75 (m, 2H); 3.45 (m, 2 H); 3.61 (m, 2H); 3.67 (m, 4 H); 4.0-4.2 (m, 1 H).

Compound 84 (1.54 g; 2.45 mmol) in solution in dioxane (15 ml) it was treated with 12 N HCl (4 ml) at 0 ° C. After stir at room temperature for 2 hours, the mixture was evaporated and triturated in ether to give compound 85 as a solid.

Yield: 100%

1 H NMR (DMSO): 1.28-1.34 (m, 2H); 1.42-1.45 (m, 3H); 1.79 (d, 2H); 2.32 (t, 2H); 2.7-2.85 (m, 2H); 3.20 (d, 2H); 3.41 (m, 4 H); 4.5-4.6 (m, 4H); 8.71 (broad m, NH).

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Example 31 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [4- (cyclobutylcarbonylaminomethyl) piperidin-1-ylmethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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198

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A mixture of compound 29 (0.115 g; 0.25 mmol), compound 87 (0.116 g, 0.5 mmol), K 2 CO 3 (0.07 g; 0.5 mmol) in acetonitrile (2 ml) and DMF (0.5 ml) was heated to 85 ° C for 3 hours under argon. The crude mixture was purified by flash chromatography eluting successively with AcOEt / 50/50 methylene chloride, AcOEt and NH3 3.5 N in MeOH / AcOEt 10/90 to give after trituration in ether / pentane the compound of example 31 in the form of a solid.

Yield: 90%

1 H NMR (CDCl 3) (δ ppm) 1.26-1.32 (m, 6H); 1.45-1.75 (m, 8H); 1.61 (s, 6H); 1.8-2.3 (m, 8H); 2.34 (s, 6H); 2.6-2.75 (broad s, 2H); 2.9-3.15 (m, 6H); 4.1 (broad s, 1H); 4.75 (broad s, 1H); 5.45 (broad s, 1H); 6.72 (s, 1 H); 6,944 (s, 1 H); 7.058 (s, 2H); 8.19 (s, 1 H). ESI-MS: 615 [M + H] +

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The starting material was prepared as follow:

199

Was added 1-tert-butoxycarbonyl-4-aminomethyl-piperidine (0.645 mg; 3 mmol), under argon, to a stirred solution of Cyclobutane-carboxylic acid (0.3 g; 3 mmol), EDC (0.864 g; 4 mmol), DIEA (0.78 ml; 4.5 mmol) and DMAP (0.055 g; 0.45 mmol) in methylene chloride (30 ml). The mixture was stirred for one overnight, it was evaporated and purified by flash chromatography, it was eluted successively with methylene chloride, AcOEt and NH3 3.5 N in MeOH / AcOEt 10/90 to give the compound as a solid.

Yield: 56%

1 H NMR (CDCl 3) 1.23 (m, 2H); 1.44 (s, 9H); 1.61-1.65 (m, 3H); 1.80-2.30 (ms, 6H); 2.68 (width, 2H); 2.98 (m, 1 H); 3.12 (broad s, 2H); 4.12 (wide s, 2H); 5.42 (wide s, 1H).

Compound 86 (0.44 g; 1.35 mmol) was dissolved in dioxane (3 ml) and treated with a solution of 12 N HCl / dioxane 5/25 (3 ml). The mixture was heated at 55 under argon. All night long. After evaporation to dryness, the residue was triturated in a mixture of MeOH, methylene chloride and ether to give compound 87 as a solid.

Yield: 69%

1 H NMR (DMSO-d 6) 1.25 (m, 2H); 1.60-1.80 (m, 4H); 1.87 (m, 1 H); 1.99 (m, 2H); 2.08 (2H); 2.77 (m, 2 H); 2.80-3.05 (m, 3H); 3.37 (m, 2H).

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200

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Example 32 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {isopropylsulfonylaminomethyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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201

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The compound of example 32 was prepared following a method described in example 31.

Yield: 88%

1 H NMR (CDCl 3): 1.25-1.40 (m, 4H); 1.38 (d, 6H); 1.45 -1.80 (m, 7H); 1.62 (s, 6H); 1.90-2-10 (broad s, 2H); 2.35 (s, 6H); 2.6-2.80 (broad s, 2H); 2.90-3.15 (m, 8H); 3.15 (s, 1 H); 4.10 (s wide, 2H); 4.75 (broad s, 1H); 6.75 (s, 1 H); 6.95 (s, 1 H); 7.05 (s, 2H); 8-16 (s, 1 H).

EM-ESI: 639 [M + H] +

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The starting material was prepared as follow:

The compound of example 32 was prepared following a method described in example 31.

Yield: 88%

1 H NMR (CDCl 3): 1.25-1.40 (m, 4H); 1.38 (d, 6H); 1.45 -1.80 (m, 7H); 1.62 (s, 6H); 1.90-2 (s wide, 2H); 2.35 (s, 6H); 2.6-2.80 (broad s, 2H); 2.90-3.15 (m, 8H); 3.15 (s, 1 H); 4.10 (wide s, 2H),  4.75 (broad s, 1H); 6.75 (s, 1 H); 6.95 (s, 1 H); 7.05 (s, 2H); 8.16 (s, 1H).

EM-ESI: 639 [M + H] +

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The starting material was prepared as follow:

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202

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Isopropylsulfonyl chloride (0.230 ml; 2.05 mmol) was added under argon at 0 ° C to a solution of 1- t -butoxycarbonyl-4-aminomethyl-piperidine (0.4 g; 1.87 mmol) and K 2 CO 3 (0.285 2.05 mmol) in acetonitrile (15 ml). The mixture was stirred overnight at room temperature and purified by flash chromatography eluting successively with methylene chloride, AcOEt / 80/20 methylene chloride to give compound 88 as a solid.

Yield: 41%

1 H NMR (CDCl 3) 1.13 (m, 2H); 1.38 (d, 6H); 1.45 (s, 9H); 1.60-1.80 (m, 3H); 2.68 (s wide, 2H), 3.04 (m, 2H); 3.16 (m, 1 H); 4.06-4.20 (s wide, 3H).

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Compound 88 (0.340 g; 0.94 mmol) was dissolved in dioxane (3 ml) / methylene chloride (0.3 ml) and treated with a 12 N HCl solution / 5/25 dioxane (2 ml). The mixture was stirred at room temperature in argon atmosphere overnight. After evaporation to dryness, the residue was triturated in a mixture of MeOH, methylene chloride and ether to give compound 89 in the form of a solid.

Yield: 100%

1 H NMR (CDCl 3) 1.35 (d, 6H); 1.66 (m, 2H); 1.81 (broad s, 1H); 1.92 (m, 2 H); 3.08 (m, 2 H); 3 (m, 1 H); 3.51 (m, 2H).

203

Example 33 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {isopropoxycarbonylaminomethyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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204

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Chloroformate was added 4-nitrophenyl (0.115 g; 0.55 mmol) under an atmosphere of argon at 0 ° C, to a solution of compound 91 (0.284 g; 0.5 mmol) and triethylamine (0.135 ml; 1.05 mmol) in methylene chloride (12 ml); after stirring at room temperature for 1 hour and evaporation, isopropanol (10 ml) was added. The mixture was maintained at reflux for 7 hours, evaporated to dryness and purified by reverse phase chromatography eluting with a gradient of MeOH / (NH 4) 2 CO 3 -H 2 O 2 g / l 10-80% to give after crushing with pentane-ether the compound of example 33 in the form of a solid.

Yield: 52%

1 H NMR (CDCl 3): 1.22 (d, 6H); 1.20-1.35 (m, 6H); 1.45-1.85 (m, 7H); 1.60 (s, 6H); 2.01 (broad s, 2H); 2.35 (s, 6H); 2.66 (s wide, 2H); 2.90-3.12 (m, 6H); 4.10 (broad s, 1H); 4.67 (m, 2H); 4.89 (m, 1 H); 6.74 (s, 1 H); 6.94 (s, 1 H); 7.06 (s, 2H); 8.13 (s, 1H).

EM-ESI: 619 [M + H] +

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The starting material was prepared as follow:

1 H NMR (CDCl 3): 1.22 (d, 6H); 1.20-1.35 (m, 6H); 1.45-1.85 (m, 7H); 1.60 (s, 6H); 2.01 (broad s, 2H); 2.35 (s, 6H); 2.66 (s wide, 2H); 2.90-3.12 (m, 6H); 4.10 (broad s, 1H); 4.67 (m, 2H); 4.89 (m, 1 H); 6.74 (s, 1 H); 6.94 (s, 1 H); 7.06 (s, 2H); 8.13 (s, 1H).

EM-ESI: 619 [M + H] +

The starting material was prepared as follow:

205

A mixture of compound 29 (3.27 g; 7.2 mmol), 4-tert-butoxycarbonylaminomethyl-piperidine  (03.08 g, 14.2 mmol), K2CO3 (1.95 g; 14.2 mmol) in acetonitrile (50 ml) and DMF (0.5 ml) was heated at 85 ° C for 3 hours in argon atmosphere. The crude mixture was purified by instant chromatography eluting successively with AcOEt / chloride of 50/50 methylene, AcOEt and NH3 3.5 N in MeOH / AcOEt 20/80 for give compound 90 as a solid.

Yield: 80%

1 H NMR (CDCl 3) 1.26-1.40 (m, 6H); 1.44 (s, 9H); 1.45-1.75 (m, 7H); 1.59 (s, 6H); 2.00 ((2H); 2.35 (s, 6H); 2.66 (m, 2 H); 2.93-3.49 (ms, 6H); 4.10 (s width, 1H); 4.61 (broad s, 1H); 4.7: wide s, 1H); 6.74 (s, 1 H); 6.94 (s, 1 H); 7.06 (s, 2H); 8.13 (s, 1 H).

Compound 90 (3.06 g; 4.84 mmol) was dissolved in dioxane (13 ml) and treated with a solution of 12 N HCl / dioxane 5/25 (9.7 ml). The mixture was stirred at room temperature in Argon atmosphere overnight. After evaporation until dryness, the residue was triturated in a mixture of MeOH, chloride methylene and ether to give compound 91 as a solid.

Yield: 100%

1 H NMR (DMSO-d 6) 1.26-1.45 (m, 6H); 1.40-1.70 (m, 7H); 1.52 (s, 6H); 1.80-2.00 (m, 3 H); 2.00 (m, 2 H); 2.34 (s, 6H); 2.66 (m, 2 H); 3.60 (m, 2 H); 4.1 (broad s, 1H); 4.55 (s width, 1H); 4.75 (broad s, 1H); 6.95 (s, 1 H); 6.98 (s, 1 H); 7.10 (s, 2H); 8.07 (s, 1 H).

Example 34 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {tetrahydrofuran-2-ylcarbonylaminomethyl} piperidin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

206

To an acid suspension tetrahydro-3-furoic (0.029 g; 0.25 mmol) in methylene chloride (2 ml), DIEA (0.190 ml; 1.09 was added mmol), HATU (0.104 g; 0.275 mmol) and compound 91 (0.146 g; 0.25 mmol). The mixture was stirred at room temperature overnight. The crude mixture was purified by flash chromatography eluting successively with 50/50 AcOEt / methylene chloride, and 3.5 N NH3 in MeOH / AcOEt 5/95 to give the compound of example 34 as a solid.

Yield: 83%

1 H NMR (CDCl 3): 1.20-1.45 (m, 6H); 1.45-1.85 (m, 7H); 1.61 (s, 6H); 2.00 (m, 2 H); 2.16 (m, 2H); 2.34 (s, 6H); 2.64 (m, 2H); 2.90 (m, 3 H); 3.01 (m, 2H); 3.16 (t, 2H); 3.80 (m, 1 H); 3.90 (m, 2H); 3.94 (m, 1 H); 4.10 (broad s, 2H); 4.75 (broad s, 1H); 6.74 (s, 1 H); 6.94 (s, 1 H); 7.05 (s, 2H); 8.15 (s, 1 H).

EM-ESI: 631 [M + H] +

Examples 34.1-34.6

Following a procedure similar to that described in example 34, the compounds of table 34 were prepared.

TABLE 34

207

Example 35 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {pyrrolidin-1-ylcarbonylmethyl} piperidin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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208

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Chloroformate was added 4-nitrophenyl (0.056 g; 0.275 mmol) under an atmosphere of argon at 0 ° C, to a solution of compound 91 (0.250 g; 0.25 mmol) and triethylamine (0.074 ml; 0.525 mmol) in methylene chloride (3 ml); After stirring at room temperature for 1 hour, it was added pyrrolidine (0.023 ml). The mixture was stirred at room temperature. overnight, it was evaporated to dryness and purified by instant chromatography eluting with NH3 3.5 N in MeOH / methylene chloride 6/94 to give the compound of example 35 in the form of a solid.

Yield: 78%

1 H NMR (CDCl 3): 1.20-1.35 (m, 4H); 1.45-1.75 (m, 4H); 1.64 (s, 6H); 1.45-1.95 (m, 10H); 2.03 (m, 2M); 2.36 (s, 6H); 2.60 (m, 2 H); 3.12 (m, 2H); 3.18 (m, 6H); 3.54 (m, 2H); 4.18 (broad s, 1H); 4.70 (broad s, 1H); 6.90 (s, 1 H); 6.93 (s, 1 H); 7.03 (s, 2H); 8.55 (s, 1 H).

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Examples 35.1-35.4

Following a procedure similar to that described in example 35, the compounds of table 35 were prepared.

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209

Example 36 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {N, N-dimethylaminocarbonyl} piperidin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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210

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A mixture of compound 93 (0.137 g, 0.25 mmol), HATU (0.152 g; 0.4 mmol) and DIEA (0.09 ml; 0.5 mmol) in DMF (2 ml) was stirred at room temperature for 2 hours. The material crude was purified on reverse phase silica eluting with a gradient of acetonitrile / acetic acid-H2O 1%, at 10-80%. The appropriate fractions evaporated and triturated in ether to give the compound of example 34 as of a solid.

Yield: 54%

1 H NMR (DMSOd 6): 1.25-1.75 (m, 8H); 1.61 (s, 6H); 1.9-2.1 (m, 4H); 2.37 (6H); 2.9-3.24 (m, 13H); 3.45-3.5 (m, 2H); 4.0-4.2 (m wide, 1H); 4.6-4.8 (m, 1 H); 6.77 (s, 1 H); 6.98 (s, 1 H); 7.05 (m, 2H).

EM-ESI: 575 [M + H] +

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The starting material was prepared as follow:

211

A mixture of compound 29 (4.55 g; 0.01 mol), 4-ethoxycarbonyl-piperidine (2.36 g; 0.015 mol), triethylamine (1.53 ml; 0.011 mol) and NaI (1.5 g; 0.01 mol) in DMA (45 ml) was heated at 110 ° C under argon for  4 hours. After extraction with ethyl acetate and evaporation, The mixture was purified by flash chromatography, eluting with a gradient of ethyl acetate / petroleum ether at 80-100% to give compound 92.

Yield: 62%

1 H NMR (CDCl 3): 1.25 (t, 3H); 1.2-1.45 (m, 4H); 1.5-1.8 (m, 4H); 1.62 (s, 6H); 1.7-2 (m, 4H); 2.05-2.15 (m, 2H); 2.25-2.35 (m, 1 HOUR); 2.35 (s, 6H); 2.64-2.67 (m, 2H); 2.93-2.98 (m, 4H); 4.13 (q, 2H); 4.0-4.2 (broad m, 1H); 4.6-4.8 (m width, 1H); 6.74 (s, 1 H); 6.94 (s, 1 H); 7.07 (s, 2H); 8.13 (s, 1 HOUR).

A solution of compound 92 (3.61 g; 0.627 mmol) in 2N NaOH (5 ml) and EtOH (100 ml) was heated at 60 ° C for 2 hours. After extraction with methylene chloride / methanol (50/50) and evaporation, the residue was triturated in ether to give the compound 93 in the form of a solid.

Yield: 93%

1 H NMR (DMSOd 6, AcOH): 1.30 (m, 4H); 1.40-1.70 (m, 4H); 1.53 (s, 6H); 1.80-2.00 (m, 4H); 2.05 (m, 2H); 2.34 (s, 6H); 2.65 (m, width, 1H); 3.14 (m, 2H); 3.27 (m, 2 H); 3.30-3.60 (m, 2H); 4.10 (m, width, 1H); 4.50 (m, width, 1H); 6.96 (m, 2H); 7.09 (m, 2H).

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Examples 36.1-36.8

Following a procedure similar to that described In Example 36, the compounds of Table 36 were prepared.

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TABLE 36

212

213

Example 37

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2- [N, N-Dibutylaminocarbonyl] -4- [2- (4- {pyrrolidin-1-ylcarbonylmethyl} piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2 , 3- b ] pyrrole

214

To a stirred solution of compound 94 (0.10 g; 0.161 mmol), dibutylamine (0.062 g; 0.483 mmol) and DIPEA (0.062 g; 0.483 mmol) in DMF (1 ml) at room temperature, HATU was added solid (0.183 g; 0.483 mmol) in one portion. Reaction mixture allowed to stand for 1 hour after which HPLC showed that there was no starting material. The reaction mixture was purified by preparative CL-EM (standard basic system) to provide the compound of example 37 (0.018 g) as a beige solid.

Yield: 18%

EM-ESI: 606 [M + H] +

1 H NMR (CDCl 3) 0.96 (t, 6H); 1.34-1.43 (m, 4H); 1.65-1.73 (m, 4H); 1.85 (m, 2 H); 1.96 (m, 2 H); 2.37 (s, 6H); 2.5-2.73 (m, 8H); 2.97 (m, 2H); 3.13 (s, 2H); 3.46-3.60 (m, 4H); 6.94 (s, 1 H); 7.08 (s, 2H); 7.40 (s, 1 H); 8.27 (s, 1 H).

Intermediate 94 was prepared as follow:

215

To a stirred solution of potassium dichromate (35.1 g; 143 mmol) in 5 N H 2 SO 4 (375 ml) at 0 ° C, was added 2-formyl-5-nitrothiophene solid (50.0 g; 318 mmol). The resulting suspension was heated to 100 ° C for 1 hour after which HPLC showed no Starting material remained. The reaction mixture was cooled to room temperature, diluted with water (300 ml) and the precipitate resulting was collected by filtration, washed with water (5 x 200 ml) and dried to a constant weight in a vacuum oven at 40 ° C to provide compound 95 (39.5 g) as a green solid Sure.

Yield: 72%

1 H NMR (DMSO-d 6) 7.70 (d, 1 H); 8.09 (d, 1 H).

To a stirred solution of compound 95 (40.0 g; 230 mmol) in DMF-acetone (1: 5, 200 ml) at -10 ° C, potassium carbonate (95.8 g; 694 mmol) was added followed by dimethyl sulfate (43.6 g; 346 mmol) dropwise 10 minutes long. The acetone was removed by evaporation and the resulting suspension was stirred at room temperature for 4 hours after which HPLC showed that there was no left Starting material. The reaction mixture was cooled to 5 ° C and was added water (1 liter) giving a thick precipitate, which was collected by filtration, washed with water (2 x 200 ml) and dried to a constant weight in a vacuum oven to provide the compound 96 (38.3 g) in the form of a beige solid.

Yield: 89%

1 H NMR (DMSO-d 6) 3.85 (s, 3H); 7.74 (d, 1 H); 8.21 (d, 1 H).

To a stirred solution of compound 96 (35 g; 187 mmol) in MeOH (400 ml) a palladium suspension was added on 10% carbon (30 g) in AcOH (100 ml). The suspension resulting was exposed to 1 atmosphere of hydrogen for 8 hours after which HPLC showed that there was no material left departure. The catalyst was filtered off through a Celite pad and the filtrate was evaporated to dryness and the residue was purified by flash chromatography on silica gel eluting with DCM-MeOH (98: 2) to provide the amine (11.4 g) in the form of an off-white solid, which was used immediately in the next stage. To a stirred solution of the amine (11.4 g; 72.9 mmol) in THF (20 ml) was added dicarbonate di-tert-butyl ((Boc) 2 O) (17.5 g; 80.2 mmol). The resulting solution is heated to reflux for 3 days after which by HPLC showed that there was no starting material left. The reaction mixture is evaporated to dryness and the residue obtained was triturated with ether diethyl (100 ml). The resulting precipitate was collected by filtration, washed with diethyl ether (2x50 ml) and dried to a constant weight to provide compound 97 (15.1 g) in form of an off-white crystalline solid.

Yield: 32%

EM-ESI: 258 [M + H] +

1 H NMR (DMSO-d 6) 1.53 (s, 9H), 3.74 (s, 3H); 6.55 (d, 1 H); 7.57 (d, 1 H).

To a stirred solution of compound 97 (13.2 g; 51.4 mmol) in DMF at -10 ° C in a bath of acetone-ice, a 60% suspension was added (w / w) of sodium hydride in mineral oil (2.26 g; 56.5 mmol). The resulting orange suspension was allowed to warm to temperature ambient and stirred for 1 hour. The reaction mixture was cooled. again at -10 ° C, and a solution of the compound was added 8 (10.3 g; 56.5 mmol) in DMF (50 ml) over a period of 10 minutes During the addition of the last 10 ml the suspension thickened and diethyl ether (200 ml) was added to mobilize the suspension. The resulting suspension was stirred for 2 hours. additional at room temperature after which HPLC showed that there was no starting material left. The precipitate is collected by filtration, washed with diethyl ether (3 x 100 ml) and the The filtrate was washed with water (3 x 100 ml), dried over sulfate magnesium and evaporated to provide an orange oil. He oil was dissolved in diethyl ether (300 ml), cooled to 0 ° C and added a solution of 4.0 M HCl in 1,4-dioxane to over a period of 10 minutes. The thick white precipitate resulting was collected by filtration, washed with diethyl ether (2x50 ml) and dried to a constant weight to provide the compound 98 (9.63 g) in the form of a white solid.

Yield: 61%

EM-ESI: 273 [M + H] +

To a stirred solution of compound 98 (10.0 g; 32.5 mmol) and compound 22 (7.85 g; 48.7 mmol) in 2-butanol at room temperature, zinc chloride (6.57 g; 48.7 mmol). The resulting suspension was heated at 110 ° C for 3 hours. The reaction mixture was evaporated to dryness and the residue was purified by flash gel chromatography.
of silica eluting with DCM-acetonitrile (4: 1) to provide compound 99 (7.1 g) as a beige solid.

Yield: 66%

EM-ESI: 330 [M + H] +

To a stirred solution of compound 99 (7.1 g; 21.5 mmol) in ethanol (50 ml) was added a solution of NaOH (4.3 g; 107 mmol) in water (22 ml). The resulting solution was heated to 70 ° C. for 1 hour after which HPLC showed that there was no left Starting material. The ethanol was separated on a rotary evaporator and at concentrate remaining at 5 ° C was added, with rapid stirring, HCl concentrated over a period of 10 minutes. The precipitate resulting was collected by filtration, washed with water (3 x 100 ml) and dried to a constant weight in a vacuum oven at 40 ° C to provide compound 100 (5.81 g).

Yield: 86%

EM-ESI: 316 [M + H] +

To a stirred suspension of compound 100 (5.81 g; 18.4 mmol) and potassium carbonate (3.31 g; 24.0 mmol) in DMF (100 ml) at 0 ° C, allyl bromide alone (2.45 g; 20.5 mmol) over a period of 10 minutes. The mixture of reaction was stirred at room temperature for 4 hours additional, after which HPLC showed that there was no left Starting material. The reaction mixture was triturated with water (300 ml) providing an oil. The liquid was separated by decantation and The oily residue was dissolved in diethyl ether (300 ml), washed with water (3 x 100 ml), dried over magnesium sulfate and evaporated to provide compound 101 (5.84 g; 89.4%) as a beige foam that was used without further purification.

Yield: 89%

EM-ESI: 355 [M + H]

1 H NMR (CDCl 3) 2.36 (s, 6H); 3.07 (t, 2H); 3.94 (t, 2H); 4.82 (d, 2H); 5.28 (dd, 11-1); 5.42 (dd, 1 H); 5.98-6.08 (m, 1 H); 6.97 (s, 1 H); 7.12 (s, 2H); 7.84 (s, 1 H); 8.35 (s, 1 H).

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To a stirred solution of compound 101 (5.44 g; 15.4 mmol) in acetonitrile (50 ml) at 0 ° C, CCl 4 was added (5 ml) followed by triphenylphosphine (4.49 g; 16.9 mmol). The solution resulting orange was allowed to warm to room temperature and was stirred for 4 hours, after which HPLC showed no Starting material remained. The reaction mixture was evaporated at dryness to provide an orange residue, which was purified by flash chromatography on silica gel eluting with DCM to provide compound 102 (5.02 g) as a foam orange.

Yield: 88%

EM-ESI: 371 [M + H] -

1 H NMR (CDCl 3) 2.39 (s, 6H); 3.25 (t, 2H); 3.75 (t, 2H); 4.83 (d, 2H); 5.32 (dd, 1 H); 5.44 (dd, 1 H); 6.01-6.12 (m, 1 H); 7.03 (s, 1 H); 7.08 (s, 2H); 7.86 (s, 1 H); 8.35 (s, 1 H).

To a stirred solution of compound 102 (4.20 g; 11.3 mmol) in DMA (20 ml) sodium iodide (1.69 g; 11.3 mmol), potassium carbonate (2.35 g; 17.0 mmol) and 1-pyrrolidinocarbonylmethylpiperazine (3.35 g; 17.0 mmol). The resulting suspension was heated at 85 ° C for 3 hours. after which HPLC showed that there was no material left departure. The reaction mixture was allowed to cool to temperature. ambient and triturated with water (100 ml) providing a thick beige precipitate that was collected by filtration, washed with water (3 x 20 ml) and dried to a constant weight in an oven vacuum at 40 ° C to provide compound 103 (6.03 g) that was used Without further purification.

Yield: 100%

EM-ESI: 535 [M + H] +

To a stirred solution of compound 103 (6.93 g; 11.3 mmol) in THF (60 ml) at room temperature was added morpholine (0.984 g; 11.30 mmol) and Pd (PPh3) 4 (3.91 g; 3.89 mmol). The reaction mixture was stirred at temperature. ambient for 3 hours after which HPLC showed that there was no starting material. The reaction mixture was evaporated at dryness and the residue was dissolved in MeOH (10 ml) and DIPEA was added (5 ml). The resulting solution was evaporated to dryness to Provide an orange oil. Toluene (10 ml) was added and the residue was evaporated to dryness again. The resulting orange oil triturated with diethyl ether (100 ml) providing a gray precipitate that was collected by filtration, washed with ether diethyl (2 x 10 ml) and dried to a constant weight to provide compound 94 (5.50 g) that was used without further purification.

Yield: 78%

EM-ESI: 495 [M + H] +

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Example 38 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [1S-methyl-2- (4- {pyrrolidin-1- ilcarbonylmethyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

216

To a stirred solution of compound 104 (0.27 g; 0.345 mmol) in MeOH (5 ml) at room temperature, was added solid magnesium powder (0.083 g; 3.45 mmol). The suspension resulting was vigorously stirred for 6 hours. The mixture of reaction was cooled to 5 ° C and a saturated solution of ammonium chloride (2 ml). The resulting gel was mobilized with MeOH (20 ml) and filtered. The filtrate was evaporated to dryness and the residue was dissolved in DMF (1 ml) and purified by CL Preparative-EM (standard basic system) for providing the compound of example 38 (0.132 g) in the form of a beige solid

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Yield: 61%

EM-ESI: 630 [M + H] +

1 H NMR (CDCl 3) 1.21-1.42 (m, 7H); 1.45-1.75 (m, 12H); 1.85 (m, 2 H); 1.93 (m, 2 H); 2.36 (s, 6H); 2.40-2.69 (m, 8H); 3.05 (m, 2H); 3.26 (m, 1 H); 3.48 (m, 4H); 4.08 (broad s, 1H); 4.73 (broad s, 1H); 6.75 (s, 1 H); 6.94 (s, 1 H); 7.07 (s, 2H); 8.08 (s, 1 H).

Intermediate 104 was prepared as follow:

217

To a stirred solution of compound 105 (28.6 g; 139 mmol) in 2-butanol (250 ml) at 110 ° C was added compound 21 (46.0 g; 126.4 mmol) over a period of 30 minutes The reaction mixture was maintained at 110 ° C for 2 hours. The reaction mixture was cooled to room temperature and added zinc chloride (25.8 g; 190 mmol). The dark brown solution resulting was heated at 110 ° C for an additional 3 hours, then of which HPLC showed that there was no starting material left. The solvent was removed on a rotary evaporator and the dark brown residue purified by flash chromatography on silica gel eluting with DCM-ethyl acetate (9: 1) to provide the compound 106 (14.5 g) in the form of a beige foam.

Yield: 29%

EM-ESI: 400 [M + H] +

1 H NMR (DMSO-d 6) 1.15 (t, 3H); 1.33 (d, 3H); 1.71 (s, 6H); 2.33 (s, 6H); 3.05 (m, 1 H); 4.06 (m, 2H); 4.60 (t, 1 H); 6.87 (s, 1 H); 6.93 (s, 1 H); 7.07 (s, 1 HOUR).

To a stirred solution of compound 106 (8.00 g; 20.1 mmol) in ethanol (200 ml) an aqueous solution of 1 N NaOH (100 ml). The resulting solution was heated at 70 ° C for 3 hours, after which HPLC showed that there was no left Starting material. The ethanol was separated on a rotary evaporator and the remaining aqueous solution was cooled to 5 ° C and acidified to pH 1 by addition of concentrated HCl. The resulting precipitate was collected by filtration, washed to neutral pH with water (5 x 50 ml) and dried to a constant weight to provide compound 107 (7.46 g) in the form of a brown solid that was used without further purification.

Yield: 100%

EM-ESI: 372 [M + H] +

1 H NMR (CDCl 3) 1.32 (d, 3H); 1.73 (s, 6H); 2.33 (s, 6H); 3.26 (m, 1 H); 3.80 (m, 3 H); 6.94 (s to be overlap, 2H); 7.08 (s, 2H); 8.12 (s, 1 H).

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To a stirred solution of compound 107 (7.46 g; 20.0 mmol) in DCM (200 ml) at 0 ° C, DIPEA (10.4 g; 80.0 mmol) and the compound 27.HCl (2.64 g; 20.0 mmol). Later added solid HATU (11.5 g; 30.2 mmol) in portions along A period of 5 minutes. The resulting orange solution was left heat to room temperature and stirred for 1 hour, then of which HPLC showed that there was no starting material left. The reaction mixture was diluted with DCM (100 ml), washed with HCl 1 N (2 x 20 ml), water (2 x 20 ml), dried over magnesium sulfate and evaporated to dryness to provide compound 108 (7.46 g) in the form of a beige solid that was used without further purification.

Yield: 83%

EM-ESI: 451 [M + H] +

To a stirred solution of compound 108 (7.6 g; 16.9 mmol) in THF (50 ml) at room temperature was added pyridinium p-toluenesulfonate (PPTS) (0.850 g; 3.4 mmol) and 3,4-dihydropyran (DHP) (4.62 g; 0.7 mmol). The resulting solution was heated at reflux for 3 hours later. of which HPLC showed that there was no starting material left. The solvent was removed by evaporation and the residue was purified by flash chromatography on silica gel eluting with DCM-ethyl acetate (4: 1) to provide the compound 109 (7.20 g).

Yield: 80%

EM-ESI: 535 [M + H] +

To a stirred solution of compound 109 (7.0 g; 13.1 mmol) in THF (100 ml) at -10 ° C was added a 60% suspension (w / w) of sodium hydride in mineral oil (0.682 g; 17.0 mmol) followed by solid p-toluenesulfonyl (2.75 g; 14.4 mmol) at over a period of 10 minutes. The reaction mixture was left. heat to room temperature and stirred for 3 hours later of which HPLC indicated complete conversion into the compound 110. Concentrated HCl and the resulting solution were added dropwise stirred for a further 2 hours at room temperature after which HPLC indicated the complete conversion of compound 110 into 111. The solvent was removed on a rotary evaporator and the residue was partitioned between water (100 ml) and DCM (300 ml). The organic layer is washed with a saturated aqueous solution of sodium bicarbonate (100 ml), brine (2 x 50 ml), dried over magnesium sulfate and evaporated to dryness to provide a white foam. The foam was triturated with diethyl ether (30 ml) and the mobile solid resulting was collected by filtration, washed with diethyl ether (4 10 ml) and dried to a constant weight in a vacuum oven at 40 ° C to provide compound 111 (2.12 g), which was used without more purification

Yield: 27%

EM-ESI: 605 [M + H] +

1 H NMR (DMSO-d 6) 1.06 (d, 3H); 1.20-1.50 (m, 8H); 1.57 (s, 6H); 2.26 (s, 6H); 2.50 (m, 1 H); 3.05 (m, 2M); 3.26 (m, 1 H); 3.48 (m, 4 H); 4.00 (s wide, 1H); 4.50 (broad s, 1H); 6.65 (broad s, 1H); 6.73 (s width, 1H); 6.85 (s, 1 H); 7.06 (s, 1 H); 7.22 (d, 2H); 7.34 (d, 2H).

To a stirred solution of compound 111 (1.0 g; 1.66 mmol) in acetonitrile (5 ml) at room temperature, was added CCl 4 (0.5 ml) followed by triphenylphosphine (0.482 g; 1.82 mmol). The resulting suspension was stirred at room temperature for 3 hours after which the HPLC indicated that there was no material left of departure. The solid was collected by filtration, washed with cold acetonitrile and dried to a constant weight to provide compound 112 (0.542 g) as a solid White.

Yield: 53%

EM-ESI: 623 [M + H] +

To a stirred suspension of compound 112 (0.45 g; 0.721 mmol), potassium carbonate (0.50 g; 3.62 mmol) and iodide sodium (0.106 g; 0.721 mmol) in DMA (2 ml) at room temperature, was added 1-pyrrolidinocarbonylmethyl-piperazine  (0.712 g; 3.62 mmol). The resulting suspension was heated to 110 ° C for 12 hours after which the HPLC showed that there was no left Starting material. The reaction mixture was triturated with water (20 ml) and the resulting beige precipitate was collected by filtration, washed with water (2 x 10 ml) and dried to a constant weight. He The resulting solid was dissolved in DCM (3 ml) and purified by instant chromatography eluting with DCM-MeOH (98: 2) to provide compound 104 (0.270 g) in the form of a beige solid

Yield: 48%

EM-ESI: 784 [M + H] +

Example 39 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- (2- (3-oxo-4- {pyrrolidin-1- ilcarbonylmethyl} piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

218

To a stirred solution of compound 22 (0.30 g; 0.66 mmol) in DMA (3 ml) at room temperature were added potassium carbonate (0.27 g; 1.98 mmol) and compound 134 (0.42 g; 1.98 mmol). The resulting suspension was heated at 130 ° C for 8 hours after which the HPLC showed that there was no material left departure. The reaction mixture was cooled to room temperature and triturated with water (10 ml). The resulting precipitate was collected by filtration, washed with water (2 x 5 ml) and dried. Solid The resulting beige was dissolved in DCM (3 ml) and purified by flash chromatography on silica gel eluting with DCM-methanol (95: 5) to provide the compound from example 39 (0.12 g) in the form of a white foam.

Yield: 25%

EM-ESI: 630 [M + H] +

1 H NMR (CDCl 3) 1.25-1.39 (m, 4H); 1.45-1.76 (m, 10H); 1.84 (m, 2 H); 1.95 (m, 2H); 2.37 (s, 6H); 2.72 (m, 2H); 2.79 (m, 2H); 2.96 (m, 2H); 3.28 (s, 2 H); 3.38 (m, 6H); 4.12 (2 s to be overlap, 3H); 4.75 (broad s, 1H); 6.73 (broad s, 1H); 6.94 (s, 1 HOUR); 7.04 (s, 2H); 8.14 (s, 1 H).

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Intermediate product 116 was prepared as follow:

219

To a stirred solution of pyrrolidine (1.0 g; 14.1 mmol) and triethylamine (1.57 g; 15.5 mmol) in DCM (20 ml) at -10 ° C, chloroacetyl chloride (1.52 g; 13.4 mmol) over a period of 10 minutes. Reaction mixture diluted with DCM (20 ml) and washed with 2N HCl (2 x 10 ml), water (2 10 ml) and dried over magnesium sulfate. The organic layer is evaporated to dryness to provide compound 113 (1.30 g).

Yield: 66%.

1 H NMR (CDCl 3) 1.88 (m, 4H); 1.95 (m, 2H); 3.50 (m, 4 H); 4.03 (s, 2H).

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To a stirred solution of piperazin-2-one (2.0 g; 19.9 mmol) and triethylamine (2.42 g; 23.9 mmol) in THF (20 ml) at -10 ° C in an acetone-ice bath, solid triphenylmethyl (5.57 g; 19.9 mmol) over a period 5 minutes The reaction mixture was allowed to warm to temperature. ambient and stirred overnight, after which HPLC does not showed remaining starting material. The solvent was separated in a rotary evaporator and the resulting white solid was washed with diethyl ether (3 x 50 ml), water (4 x 50 ml) and dried to a constant weight in a vacuum oven to provide compound 114 (6.8 g) in Shape of a white solid.

Yield: 100%

1 H NMR (CDCl 3) (δ ppm) 2.50 (m, 2H); 3.11 (m, 2H); 3.46 (s, 2 H); 5.93 (s, 1 H); 7.21 (m, 3 H); 7.31 (m, 7H); 7.35 (m, 5H).

To a stirred solution of compound 114 (1.0 g; 5.84 mmol) in DMF (50 ml), a 60% suspension (w / w) of NaH in mineral oil (0.26 g; 6.43 mmol) at 0 ° C. The mixture of reaction was allowed to stir for 1 hour at 0 ° C before adding the compound 113 (0.864 g; 5.84 mmol) in portions along a 5 minute period. The resulting solution was allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was cooled to 0 ° C, triturated with water (100 ml) and the resulting precipitate was collected by filtration, washed with water (3 x 20 ml) and dried to a constant weight to provide compound 115 (2.20 g) in the form of a white solid that was used Without further purification.

Yield: 83%.

1 H NMR (CDCl 3) 1.83 (m, 2H); 1.97 (m, 2H); 2.46 (m, 2 H); 3.15 (m, 2H); 3.46 (m, 4 H); 3.49 (m, 2 H); 4.12 (s, 2H); 7.17 (m, 3 H); 7.27 (m, 7H); 7.46 (m, 5H).

To a stirred solution of compound 115 (2.2 g; 4.80 mmol) in MeOH (20 ml) at room temperature, HCl was added concentrated (2 ml) in one serving. The reaction mixture was stirred at room temperature for 1 hour after which by TLC (SiO2, DCM) it was shown that no starting material remained. He solvent was removed on a rotary evaporator to provide a residue oily orange Toluene (50 ml) was added and the suspension resulting evaporated to dryness to provide an orange oil thick that was dried under high vacuum to provide the compound 116 (1.2 g; 100%) in the form of an orange foam that was used without further ado purification.

Yield: 100%

Example 40 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {4-oxo-4-pyrrolidin- 1-ilbut-3-yl} piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

220

To a stirred solution of compound 18 (0.30 g; 0.595 mmol) in DMF (1 ml) compound 117 (0.23 g; 1.19 was added mmol). The reaction mixture was heated at 130 ° C for 8 hours, after which HPLC showed that there was no material left departure. The reaction mixture was purified by chromatography. snapshot on silica gel eluting with DCM-MeOH (96: 4) to provide the compound of example 40 (0.09 g) in Shape of a beige solid.

Yield: 24%

EM-ESI: 644 [M + H] +

1 H NMR (CDCl 3) 0.83 (t, 3H); 1.17 (m, 2H); 1.25-1.39 (broad m, 4H); 1.45-1.76 (m, 8H); 1.84 (m, 2 H); 1.91 (m, 6H); 2.33 (s, 6H); 2.46-2.79 (m, 8H); 2.94 (m, 2H); 3.14 (m, 1 HOUR); 3.45 (m, 3 H); 3.65 (m, 1 H); 4.10 (broad s, 1H); 4.74 (wide s, 1 HOUR); 6.73 (s, 1 H); 6.92 (s, 1 H); 7.04 (s, 2H); 8.16 (s, 1 H).

Intermediate 117 was prepared as follow:

221

To a stirred suspension of pyrrolidine (1.0 g; 14.1 mmol) and triethylamine (1.57 g; 15.5 mmol) in DCM (20 ml) at -10 ° C, 2-Chlorobutyryl (1.80 g; 12.7 mmol) along a 10 minute period. The reaction mixture was allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was diluted with DCM (20 ml) and washed with 2N HCl (10 ml), water (2 x 10 ml), dried magnesium sulfate sachets and dried evaporated to dryness on a rotary evaporator to provide the compound 117 (1.2 g).

Yield: 54%

1 H NMR (CDCl 3) 1.03 (t, 3H); 1.61 (m, 2H); 1.84-2.01 (m, 4H); 2.10 (m, 1 H); 3.45 (m, 2 H); 3.66 (m, 1 H); 4.21 (m, 1 H).

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Example 41 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {3-oxo-3-pyrrolidin- 1-ilprop-2-yl} piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

222

Starting from compound 18 (0.40 g; 0.774 mmol) using a procedure similar to that described for the synthesis of compound of example 40, the compound of example 41 was obtained (0.12 g) in the form of an off-white solid.

Yield: 24%

EM-ESI: 630 [M + H] +

1 H NMR (CDCl 3) 1.19 (d, 3H); 1.20-1.40 (wide m, 4H); 1.45-1.78 (m, 12H); 1.82 (m, 2 H); 1.91 (m, 2 H); 2.33 (s, 6H); 2.44-2.71 (m, 8H); 2.92 (m, 2H); 3.34 (m, 1 H); 3.44 (m, 3H); 3.72 (m, 1 H); 4.10 (broad s, 1H); 4.74 (broad s, 1H); 6.72 (s, 1 H); 6.93 (s, 1 H); 7.03 (s, 2H); 8.21 (s, 1 H).

Starting from pyrrolidine (1.0 g; 14.1 mmol) and suitable acid chloride using a similar procedure described for the synthesis of compound 117, the compound was obtained 118 (1.47 g) in the form of a yellow oil.

Yield: 57%

1 H NMR (CDCl 3) 1.65 (d, 3H); 1.86 (m, 2H); 1.95 (m, 2H); 3.5 (m, 3H); 3.69 (m, 1 H); 4.47 (m, 1 H).

Example 42 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {pyrrolidin-1-ylcarbonylmethyl} piperazin- 1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2.2.1] 3- b ] pyrrole

223

To a solution of compound 119 (0.20 g; 0.30 mmol), and compound 120.HCl (0.123 g; 0.901 mmol) and DIPEA (0.116 g; 0.901 mmol) in DMF (1 ml) at room temperature, HATU was added solid (0.343 g 0.901 mmol) in one portion. Reaction mixture allowed to stand for 1 hour after which HPLC showed that there was no starting material. The reaction mixture was purified by preparative CL-EM (standard basic system) to provide the compound of example 42 (0.070 g) as a beige solid.

Yield: 37%

EM-ESI: 630 [M + H] +

1 H NMR (CDCl 3) 1.34-1.69 (m, 20H); 1.85 (m, 2 H); 1.94 (m, 2 H); 2.34 (s, 6H); 2.5-2.73 (m, 8H); 2.95 (m, 2H); 3.13 (s, 2H); 3.46-3.53 (m, 4H); 6.67 (s, 1 H); 6.94 (s, 1 H); 7.06 (s, 2H); 8.12 (s, 1 H).

Intermediate 119 was prepared as follow:

224

To a stirred suspension of compound 24 (5.0 g; 14.0 mmol) and potassium carbonate (2.48 g; 18.0 mmol) in DMF (50 ml) at 0 ° C, allyl bromide alone (1.86 g; 15.4 was added dropwise) mmol) over a period of 10 minutes. Reaction mixture stirred at room temperature for an additional 4 hours after of which HPLC showed that there was no starting material left. The reaction mixture was partitioned between water (100 ml) and ether. diethyl (300 ml). The organic layer was retained, washed with water (3 x 100 ml), dried over magnesium sulfate and evaporated to dryness to provide compound 121 (4.89 g) in the form of a beige foam that was used without further purification.

Yield: 88%

EM-ESI: 397 [M + H] +

To a stirred solution of compound 121 (4.89 g; 12.3 mmol) in acetonitrile (50 ml) at 0 ° C, CCl 4 (5 ml) followed by triphenylphosphine (4.91 g; 18.5 mmol). The solution resulting orange was allowed to warm to room temperature and was stirred for 2 hours, after which HPLC showed no Starting material remained. The reaction mixture was evaporated at dryness to provide an orange residue, which was purified by flash chromatography on silica gel eluting with DCM to provide compound 122 (2.5 g) in the form of a foam orange.

Yield: 49%

EM-ESI: 415 [M + H] +

To a stirred solution of compound 122 (2.50 g; 6.04 mmol) in DMA (20 ml) sodium iodide (0.905 g; 6.04 mmol), potassium carbonate (1.24 g; 9.06 mmol) and 1-pyrrolidinocarbonylmethylpiperazine (1.79 g; 9.06 mmol). The resulting suspension was heated at 85 ° C for 4 hours, after which the HPLC showed that there was no material left departure. The reaction mixture was allowed to cool to temperature. ambient and triturated with water (100 ml) to provide an oil. Water was separated by decantation and the oil was dissolved in DCM (100 ml), washed with water (3 x 10 ml), evaporated to dryness in a rotary evaporator and dried to a constant weight with high vacuum to provide compound 123 (2.87 g) that was used without further purification.

Yield: 82%

EM-ESI: 577 [M + H] +

To a stirred solution of compound 123 (2.87 g; 4.98 mmol) in THF (40 ml) at room temperature was added morpholine (0.409 g; 4.70 mmol) and Pd (PPh3) 4 (1.63 g; 1.91 mmol). The reaction mixture was stirred at temperature. ambient for 3 hours after which HPLC showed that there was no starting material. The reaction mixture was evaporated at dryness and the residue was dissolved in MeOH (10 ml) and DIPEA was added (5 ml). The resulting solution was evaporated to dryness to Provide an orange solid. Toluene (10 ml) was added and the residue was evaporated to dryness again. The resulting orange oil triturated with diethyl ether (50 ml) to provide a precipitate which was collected by filtration, washed with diethyl ether (2 x 10 ml) and dried to a constant weight to provide the compound 119 (2.74 g) in the form of a beige solid that was used without further ado purification.

Yield: 83%

EM-ESI 537 [M + H] +

Example 43 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {1H-1,2,3- benzotriazol-5-ylaminocarbonylmethyl} piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

225

To a solution of compound 125 (0.20 g; 0.334 mmol), 5-aminobenzotriazole (0.067 g; 0.501 mmol) and DIPEA (0.129 g; 1.0 mmol) in DMF (1 ml) at room temperature, is added solid HATU (0.191 g; 0.501 mmol) in one portion. Mix The reaction was allowed to stand for 16 hours, after which HPLC showed that there was no starting material left. The mixture of reaction was purified by preparative LC-MS (system standard acid) to provide the compound of example 43 (0.028 g) in the form of a brown solid.

Yield: 12%

EM-ESI: 679 [M + H] +

1 H NMR (DMSO-d 6) 1.24-1.33 (m, 4H); 1.35-1.56 (m, 10H); 1.88 (m, 4 H); 2.35 (s, 6H); 2.5-2.73 (m, 2H); 2.84 (m, 2 H); 3.15 (s, 2H); 3.46-3.53 (m, 4H); 4.10 (s wide, 1H); 4.45 (broad s, 1H); 6.81 (s, 1 H); 6.92 (s, 1 H); 7.09 (s, 2H); 7.43 (d, 1 H); 7.86 (d, 1 H); 8.32 (s, 1 H); 9.94 (s, 1 H); 11.26 (s, 1 H).

Intermediate 125 was prepared as follow:

226

To a stirred suspension of compound 18 (6.82 g; 13.5 mmol) and potassium carbonate (2.43 g; 17.6 mmol) in DMF (20 ml) at room temperature, bromoacetate was added t-butyl (2.64 g; 13.5 mmol). Orange suspension resulting was heated at 50 ° C for 2 hours after which the HPLC showed that there was no starting material left. The mixture of reaction was cooled to 0-5 ° C and water (300 ml) producing a thick precipitate, which was collected by filtration, washed with water (3 x 50 ml) and dried to a weight constant to provide compound 124 (7.0 g) in the form of a beige solid

Yield: 84%

EM-ESI: 619 [M + H] +

To a stirred solution of compound 124 (7.0 g; 11.3 mmol) in DCM (50 ml) at room temperature, HCl was added concentrated (10 ml). The reaction mixture was heated at 40 ° C for 2 hours, after which HPLC showed that there was no left Starting material. The solvent was evaporated on a rotary evaporator to provide an orange residue. Toluene (50 ml) was added and the resulting oil suspension was evaporated to dryness and dried up to a constant weight with high vacuum to provide the compound 125 (6.77 g) in the form of a beige foam that was used without more purification

Yield: 100%

EM-ESI: 563 [M + H] +

Example 44 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4-hydroxy-4- {N, N- diethylaminomethyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

227

A mixture of compound 29 (0.16 g; 0.35 mmol), compound 128 (0.153 g, 0.69 mmol), and K 2 CO 3 (0.153 g; 1.04 mmol) in acetonitrile (3 ml) and DMF (2 ml) was heated to 90 ° C in Argon atmosphere for 3 hours. The crude mixture was purified by flash chromatography eluting with MeOH-NH3 3.5 N / 95/5 methylene chloride to give after crushing in pentane the compound of example 44 in the form of a solid.

Yield: 51%

EM-ESI: 605 [M + H] +

1 H NMR (CDCl 3) 1.01 (t, 6H); 1.20-1.44 (m, 4H); 1.50-1.70 (m, 8H); 1.62 (s, 6H); 2.35 (s, 6H); 2.37 (m, 2 H); 2.45 (m, 2 H); 2.59 (q, 4H); 2.69 (m, 2 H); 2.72 (m, 2H); 2.97 (m, 2H); 4.1 (s wide, 1 HOUR); 4.61 (broad s, 1H); 4.75 (broad s, 1H); 6.76 (s, 1 H); 6.94 (s, 1 HOUR); 7.07 (s, 2H); 8.15 (s, 1 H).

The starting material was prepared as follow:

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228

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A solution of compound 126 (0.639 g; 3 mmol) and diethylamine (0.620 ml; 6 mmol) in ethanol (5 ml) was stirred for one night at room temperature in an argon atmosphere. After evaporation to dryness, the residue was purified by flash chromatography eluting with MeOH-NH3 3.5 N / 95/5 methylene chloride to give compound 127 in form of a solid.

Yield: 86%

1 H NMR (CDCl 3) 1.01 (t, 6H); 1.39 (m, 2H); 1.45 (s, 9H); 1.58 (m, 2 H); 2.34 (s, 2 H); 2.58 (q, 4H); 3.15 (wide s, 2H); 4.85 (wide s, 2H).

Compound 127 (0.465 g; 1.62 mmol) is dissolved in methylene chloride (0.8 ml) and dioxane (6 ml) and treated with a solution of 12 N HCl / 5/25 dioxane (4.5 ml). Mix stirred at room temperature, under argon for a period of night. After evaporation to dryness, the residue was triturated in a mixture of MeOH, methylene chloride and ether to give the compound 128 in the form of a solid.

Yield: 100%

1 H NMR (DMSO-d 6) 1.25 (t, 6H); 1.81 (m, 2 H); 1.96 (m, 2 H); 2.51 (s, 2 H); 3.02-3.30 (m, 6H); 3.37 (wide s, 2H).

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Example 45 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4-methoxy-4- {N, N- diethylaminomethyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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229

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The compound was prepared using a similar method. to that described in example 44 with amine 131 instead of the amine 128.

Yield: 72%

EM-ESI: 619 [M + H] +

1 H NMR (CDCl 3) 0.97 (t, 6H); 1.20-1.40 (m, 4 H); 1.40-1.85 (m, 8H); 1.63 (s, 6H); 2.35 (s, 6H); 2.37-2.55 (m, 4H); 2.57 (q, 4H); 2.85 (m, 2 H); 3.04 (m, 4 H); 3.19 (s, 3 H); 4.10 (s width, 1H); 4.70 (broad s, 1H); 6.81 (s, 1 H); 6.94 (s, 1 H); 7.04 (s, 2H); 8.18 (s, 1 H).

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The starting material was prepared as follow:

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230

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To a stirred solution of compound 129 (0.82 g; 2.6 mmol) in THF (18 ml), a 60% suspension (w / w) was added of sodium hydride in mineral oil (0.175 g). The suspension The resulting was stirred at room temperature for 3 minutes. Be added methyl iodide (0.3 ml) and ether 15-crown-5 and the reaction mixture It stirred more overnight. After evaporation until dryness, the residue was purified by flash chromatography eluting with MeOH-NH3 3.5 N / methylene chloride 97/3 to give compound 130 as a solid.

Yield: 79%

1 H NMR (CDCl 3) 0.97 (t, 6H); 1.47 (s, 9H); 1.58 (m, 2 H); 1.75 (m, 2H); 2.38 (s, 2 H); 3.05 (broad s, 2H); 3.21 (s, 3 H); 3.85 (wide s, 2H).

Compound 130 (0.680 g; 2.26 mmol) is dissolved in methylene chloride (1.2 ml) and dioxane (9 ml) and treated with a solution of 12 N HCl / 5/25 dioxane (5.5 ml). Mix stirred at room temperature under argon during a night. After evaporation to dryness, the residue was triturated in a mixture of MeOH, methylene chloride and ether to give the compound 131 in the form of a solid.

Yield: 100%

1 H NMR (DMSO-d 6) 1.24 (t, 6H); 1.80 (m, 2 H); 2.08 (m, 2H); 2.92 (m, 2H); 3.20 (s, 3 H); 3.10-3.30 (m, 8H).

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Example 46 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [4- (pyrrolidin-1-ylcarbonylmethyl) piperazin-1-ylmethyl ] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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231

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A A mixture of 1- [2- (piperazin) -1-yl) acetyl] pyrrolidine (0.065 g; 0.33 mmol) and formaldehyde (0.013 g; 0.16 mmol) in acid Acetic (5 ml) compound 32 (0.065 g; 0.17 mmol) was added in dioxane (8 ml) at room temperature. After 4 hours, the Crude mixture was evaporated and purified by flash chromatography. eluting with a gradient of NH3 3.5 N in MeOH / chloride 2-10% methylene to give after crushing  in ether / pentane the compound of example 46 in the form of a solid.

Yield: 65%

EM-ESI: 602 [M + H] +

1 H NMR (CDCl 3): 1.20-1.40 (m, 4H); 1.45-1.80 (m, 4H); 1.62 (s, 6H); 1.84 (m, 2 H); 1.94 (m, 2 H); 2.35 (s, 6H); 2.54 (wide m, 8H); 3.10 (s, 2H); 3.45-3.52 (m, 4H); 3.54 (s, 2H); 4.14 (broad m, 1H); 4.73 (broad m, 1H); 6.81 (s, 1 H); 6.94 (s, 1 H); 7.26 (s, 2H); 8.25 (s, 1 H).

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Examples 46.1-46.5

Following a procedure similar to that described in example 46, the compounds of table 46 were prepared.

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TABLE 46

232

Example 47 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [4- (2,4-dioxo-1,2,3 , 4-tetrahydropyrimidin-6-ylmethyl) piperazin-1-ylmethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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233

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A mixture of compound 132 (0.175 g; 0.35 mmol), chloromethyluracil (0.061 g; 0.38 mmol), NaI (0.057 g; 0.38 mmol) and K 2 CO 3 (0.053 g; 0.38 mmol) in dimethylacetamide (8 ml) was heated at 80 ° C under argon for 17 hours. The Crude mixture was evaporated and purified by flash chromatography. eluting with a gradient of NH3 3.5 N in MeOH / chloride 2-8% methylene to give after crushing in ether / heptane the compound of example 47 in the form of a solid pale brown

Yield: 41%

EM-ESI: 615 [M + H] +

1 H NMR (CDCl 3): 1.20-1.40 (wide m, 4H); 1.56 (broad m, 4H); 1.63 (s, 6H); 2.36 (s, 6H); 2.50 (broad m, 8H); 3.29 (s, 2 H); 3.58 (s, 2H); 4.15 (broad m, 1H); 4.75 (broad m, 1H); 5.53 (s, 1 H); 6.80 (s, 1 HOUR); 6.96 (s, 1 H); 7.21 (s, 2H); 7.97 (broad s, 1H); 8.25 (s, 1 H); 8.53 (wide s, 1H).

The compound of example 46.4 (0.878 g, 1.49 mmol) was deprotected with concentrated HCl (1.5 ml) in dioxane (15 ml) at room temperature for 4 hours. The crude mixture is evaporated, then 100 ml of 3.5 N NH 3 in MeOH was added, and It evaporated again. The crude residue was purified by chromatography. snapshot eluting with a gradient of NH 3 in MeOH 3.5 N / 0-10% methylene chloride to give the compound 132.

Yield = 100%

EM-ESI: 491 [M + H] +

1 H NMR (DMSO-d 6): 1.26 (broad m, 4H); 1.45 (broad m, 4H); 1.52 (s, 6H); 2.30 (s, 6H); 2.35 (m, 4H); 2.67 (m, 4 H); 3.41 (m, 2 H); 4.20-4.45 (m wide, 2H); 6.79 (s, 1 H); 6.90 (s, 1 H); 7.31 (s, 2H); 11.34 (s wide, 1H).

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Example 48 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [4- (morpholinocarbonyl) piperidin-1-ylmethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

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2. 3. 4

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To a mixture of compound 30 (0.058 g; 0.29 mmol) and formaldehyde (0.021 g; 0.26 mmol) in acetic acid (10 ml) Compound 32 (0.104 g; 0.27 mmol) in dioxane (20 ml) was added to room temperature. After 4 hours, the crude mixture is evaporated and purified by flash chromatography eluting with a gradient of NH3 3.5 N in MeOH / methylene chloride at 1-5% to give after crushing in ether / pentane the compound of example 48 in the form of a solid.

Yield: 98%

EM-ESI: 603 [M + H] +

1 H NMR (CDCl 3): 1.20-1.40 (m, 4H); 1.62 (s, 6H); 1.68 (m, 5 H); 1.85 (m, 2H); 2.00 (m, 2 H); 2.35 (s, 6H); 2.42 (m, 1 H); 3.05 (m, 2H); 3.47 (m, 5 H); 3.61 (m, 2H); 3.66 (m, 4H); 4.14 (broad m, 1H); 4.73 (m wide, 1H); 6.79 (s, 1 H); 6.94 (s, 1 H); 7.27 (s, 2H); 8.27 (s, 1 HOUR).

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Example 49 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (3- (4-acetylpiperazin-1-yl) pyrrolidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

235

A mixture of compound 29 (0.133 g; 0.29 mmol), compound 135 (0.063 g, 0.32 mmol), NaI (0.048 g; 0.32 mmol) and K 2 CO 3 (0.044 g; 0.32 mmol) in dimethylacetamide (3 ml) was heated at 85 ° C under argon for 4 hours. The Crude mixture was evaporated and purified by flash chromatography. eluting with a gradient of NH 3 in 3.5 N MeOH / chloride 4-8% methylene to give after crushing in ether / pentane the compound of example 49 in the form of a solid.

Yield: 52%

EM-ESI: 616 [M + H] +

1 H NMR (CDCl 3): 1.29 (m, 4H); 1.61 (s, 6H); 1.45-1.80 (m, 4H); 2.00 (m, 1 H); 2.08 (s, 3 H); 2.34 (s, 6H); 2.42 (m, 5 H); 2.48 (m, 1 H); 2.55 (m, 1 H); 2.70 (m, 1 HOUR); 2.80 (m, 2 H); 2.88 (m, 2 H); 2.93 (m, 2H); 3.46 (m, 2 H); 3.62 (m, 2H); 4.10 (broad m, 1H); 4.75 (broad m, 1H); 6.73 (s, 1 H); 6.94 (s, 1 H); 7.06 (s, 2H); 8.16 (s, 1 H).

Compound 135 was prepared as follows:

236

A mixture of compound 133 (0.461 g; 1.39 mmol) and acetyl-piperazine (0.535 g; 4.17 mmol) in dimethylformamide (1 ml) was heated to reflux under argon for 1 hour. The crude mixture was evaporated and purified by flash chromatography eluting with a gradient of NH 3 in 3.5 N MeOH / 0-3% methylene chloride to give the compound 134 in the form of an oil.

Yield: 80%

EM-ESI: 288 [M + H] +

1 H NMR (CDCl 3): 1.73 (m, 3H); 2.00 (m, 1 HOUR); 2.07 (s, 3 H); 2.30-2.50 (m, 3 H); 2.54 (m, 1 H); 2.69 (m, 1 H); 2.79 (m, 1 H); 2.88 (m, 1 H); 3.45 (m, 2 H); 3.60 (m, 4H); 7.25 (m, 2H); 7.31 (m, 3H).

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To a mixture of compound 134 (0.358 g; 1.25 mmol) in methanol (3 ml) ammonium formate (0.236 g; 3.74 mmol) and Pd / C (0.013 g, 0.125 mmol). The reaction was heated to reflux for one hour, and then filtered through celite. The crude mixture was evaporated and purified by chromatography. snapshot eluting with a gradient of NH 3 in MeOH 3.5 N / 10-20% methylene chloride to give the compound 135 in the form of an oil.

Yield: 66%

EM-ESI: 198 [M + H] +

1 H NMR (CDCl 3): 1.65 (m, 1H); 1.97 (m, 1 HOUR); 2.08 (s, 3 H); 2.08 (broad m, 2H); 2.41-2.50 (m, 3H); 2.76 (m, 2H); 2.97 (m, 1 H); 3.07 (m, 1 H); 3.12 (m, 1 H); 3.47 (m, 2H); 3.62 (m, 2H).

Examples 49.1-49.3

Following a procedure similar to that described In Example 49, the compounds of Table 49 were prepared.

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TABLE 49

237

Example 50 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (3- {morpholinocarbonyl} pyrrolidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole

238

A mixture of compound 29 (0.139 g; 0.31 mmol), compound 138 (0.062 g; 0.34 mmol), NaI (0.046 g; 0.31 mmol) and K 2 CO 3 (0.051 g; 0.37 mmol) in dimethylacetamide (3 ml) is heated at 85 ° C under argon for 3 hours. Mix crude was evaporated and purified by flash chromatography eluting with a gradient of NH3 3.5 N in MeOH / chloride 1-3% methylene to give after crushing in ether / pentane the compound of example 50 in the form of a solid White.

Yield: 62%

EM-ESI: 603 [M + H] +

1 H NMR (CDCl 3): 1.31 (m, 4H); 1.45-1.80 (m, 4H); 1.62 (s, 6H); 2.05-2.15 (m, 2H); 2.35 (s, 6H); 2.49 (m, 1 H); 2.65 (m, 1 H); 2.75 (m, 1 H); 2.82 (m, 1 H); 2.96 (m, 3 H); 3.04 (m, 1 H); 3.19 (m, 1 H); 3.48 (m, 2 H); 3.65 (m, 6H); 4.10 (broad m, 1H); 4.75 (m wide, 1H); 6.74 (s, 1 H); 6.94 (s, 1 H); 7.06 (s, 2H); 8.13 (s, 1 HOUR).

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Compound 138 was prepared as follows:

239

A mixture of compound 136 (0.127 g; 0.62 mmol), morpholine (0.081 ml; 0.93 mmol), EDCl (0.143 g; 0.74 mmol) and HOBT (0.084 g; 0.62 mmol) in methylene chloride (5 ml) was stirred at room temperature under argon for 24 hours. The Crude mixture was dissolved in ethyl acetate and washed with a 2N NaOH solution. The organic layer was dried over sulfate. magnesium, evaporated and purified by flash chromatography eluting with a gradient of NH 3 in 3.5 N MeOH / chloride 5-10% methylene to give compound 137 in form of an oil.

Yield: 75%

EM-ESI: 275 [M + H] +

1 H NMR (CDCl 3): 2.00-2.15 (m, 2H); 2.46 (q, J = 9 Hz, 1H); 2.60 (t, J = 8.5 Hz, 1H); 2.83 (m, 1 H); 2.94 (t, J = 9 Hz, 1H); 3.16 (m, 1 H); 3.47 (m, 2 H); 3.65 (m, 8H); 7.24 (m, 2H); 7.32 (m, 3H).

To a mixture of compound 137 (0.108 g; 0.30 mmol) in methanol (5 ml) ammonium formate (0.074 g; 1.18 mmol) and Pd / C (0.004 g; 0.04 mmol). The reaction was heated to reflux for 3 hours, and then filtered through celite. The Crude mixture was evaporated and purified by flash chromatography. eluting with a gradient of NH 3 in 3.5 N MeOH / chloride 20-22% methylene to give compound 138 in Shape of an oil.

Yield: 88%

EM-ESI: 185 [M + H] +

1 H NMR (CDCl 3): 2.07 (m, 2H); 3.01 (m, 1 HOUR); 3.07 (m, 1 H); 3.16 (m, 2H); 3.28 (m, 1 H); 3.53 (m, 2H); 3.62 (m, 2H); 3.67 (m, 5H).

Examples 50.1-50.3

Following a procedure similar to that described in example 50, the compounds of table 50 were prepared.

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TABLE 50

240

Example 51 2- [1,1-Dimethyl-2-oxo-2- (7-azybicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (5- t -butoxycarbonyl-octahydropyrrolo [3,4 - c ] pyrrole-2-yl) ethyl] -5- (3,5-dimethylphenyl) -6H-thieno [2,3-b] pyrrole

241

A mixture of compound 29 (0.123 g; 0.27 mmol), compound 139 (0.063 g, 0.30 mmol), NaI (0.040 g; 0.27 mmol) and K 2 CO 3 (0.045 g; 0.32 mmol) in dimethylacetamide (3 ml) was heated at 85 ° C under argon for 3 hours. The Crude mixture was evaporated and purified by flash chromatography. eluting with a gradient of NH 3 in 3.5 N MeOH / chloride 1-3% methylene to give after crushing in ether / pentane the compound of example 51 in the form of a solid White.

Yield: 78%

EM-ESI: 631 [M + H] +

1 H NMR (CDCl 3): 1.31 (m, 6H); 1.45 (s, 9H); 1.50-1.75 (m, 4H); 1.62 (s, 6H); 2.35 (s, 6H); 2.72 (m, 2H); 2.80 (m, 4 H); 2.94 (m, 2H); 3.25 (broad m, 2H); 3.55 (broad m, 2H); 4.10-4.20 (broad m, 1H); 4.70-4.80 (broad m, 1H); 6.74 (s, 1 H); 6.95 (s, 1 H); 7.07 (s, 2H); 8.12 (s, 1 H).

Examples 51.1

The compound of example 51.1 was obtained by deprotection of the compound of example 50 with HCl in dioxane.

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TABLE 51

242

Example 52 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (3- {morpholinocarbonylamino} pyrrolidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3-b] pyrrole

243

A mixture of compound 29 (0.200 g; 0.44 mmol), compound 142 (0.178 g, 0.76 mmol), NaI (0.066 g; 0.44 mmol) and K 2 CO 3 (0.243 g; 1.76 mmol) in dimethylacetamide (4 ml) was heated at 85 ° C under argon for 4 hours. The Crude mixture was evaporated and purified by flash chromatography. eluting with a gradient of NH3 3.5 N in MeOH / chloride 2-4% methylene to give after crushing in ether / pentane the compound of example 52 in the form of a solid pale brown

Yield: 42%

EM-ESI: 618 [M + H] +

1 H NMR (CDCl 3): 1.25-1.40 (m, 4H); 1.62 (s, 6H); 1.50-1.80 (m, 4H); 2.20-2.40 (m, 3H); 2.35 (s, 6H); 2.52 (m, 1 H); 2.74 (m, 3 H); 2.95 (m, 3 H); 3.32 (m, 4H); 3.67 (m, 4 H); 4.10 (broad m, 1H); 4.39 (broad m, 1H); 4.71 (m wide, 1H); 4.87 (broad m, 1H); 6.74 (s, 1 H); 6.95 (s, 1 H); 7.06 (s, 2H); 8.16 (s, 1 H).

Compound 142 was prepared as follows:

244

To a stirred solution of compound 140 (0.500 g; 2.68 mmol) in methylene chloride (10 ml), triethylamine (0.410 ml; 2.95 mmol) was added at 0 ° C and then p- nitrophenyl chloroformate (0.594 g; 2, 95 mmol). After 1 hour, morpholine (0.260 ml; 2.95 mmol) was added and the reaction mixture was stirred at room temperature under argon for 24 hours. The crude mixture was washed with water. The organic layer was dried over magnesium sulfate, evaporated and purified by flash chromatography eluting first with pure AcOEt and then with NH 3 in 3.5 N MeOH / 10% methylene chloride to give compound 141 as of a white foam.

Yield: 86%

EM-ESI: 300 [M + H] +

1 H NMR (CDCl 3): 1.46 (s, 9H); 1.75-1.90 (m, 1 H); 2.15 (m, 1 H); 3.15 (m, 1 H); 3.34 (m, 4H); 3.30-3.50 (m, 2H); 3.65 (m, 1 H); 3.69 (m, 4H); 4.30-4.50 (m, 2H).

To a solution of compound 141 (0.680 g; 2.27 mmol) in dioxane (22 ml) concentrated HCl (0.60 ml) was added. The reaction was stirred at room temperature for 7 hours, and then it was evaporated to give after trituration in chloride of methylene / ether / pentane compound 142 in the form of a brown foam pale, which was used without further characterization in the example 52

Yield: 47%

Examples 52.1-52.3

Following a procedure similar to that described in example 52, the compounds of table 52 were prepared.

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TABLE 52

245

Example 53 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl) -4- [2- (3- {1,1-dioxothiomorpholin-4- ilcarbonylmethyl} pyrrolidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6H-thieno [2,3-b] pyrrole

246

A mixture of compound 29 (0.250 g; 0.55 mmol), compound 145 (0.203 g, 0.83 mmol), NaI (0.082 g; 0.55 mmol) and K2CO3 (0.228 g; 1.65 mmol) in dimethylacetamide (3 ml) was heated at 85 ° C under argon for 4 hours. The Crude mixture was evaporated and purified by flash chromatography. eluting with a gradient of NH3 3.5 N in MeOH / chloride 2-6% methylene to give after crushing in ether / pentane the compound of example 53 in the form of a solid.

Yield: 62%

EM-ESI: 665 [M + H] +

1 H NMR (CDCl 3): 1.32 (m, 4H); 1.62 (s, 6H); 1.40-1.78 (m, 8H); 2.16 (s, 1 H); 2.35 (s, 6H); 2.52 (m, 3 H); 2.65-2.78 (m, 4H); 2.95 (m, 2H); 3.02 (m, 3H); 3.95 (m, 2H); 4.10 (broad m, 3H); 4.72 (wide m, 1H): 6.73 (s, 1 H); 6.95 (s, 1 H); 7.07 (s, 2H); 8.16 (s, 1 H).

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Compound 145 was prepared as follows:

247

A mixture of compound 143 (0.588 g; 2.54 mmol), thiomorpholine-1,1-dioxide (0.516 g; 3.82 mmol), EDCl (0.585 g; 3.05 mmol) and HOBT (0.344 g; 2.54 mmol) in methylene chloride (10 ml) was stirred at temperature atmosphere in argon atmosphere for 24 hours. The crude mixture is dissolved in ethyl acetate and washed with a solution of NaOH 2 N. The organic layer was dried over magnesium sulfate, evaporated and purified by flash chromatography eluting with a gradient of NH 3 in 3.5 N MeOH / methylene chloride at 5-10% to give compound 144 as a oil.

Yield: 82%

1 H NMR (CDCl 3): 1.43 (m, 1H); 2.13 (m, 1 HOUR); 2.27 (m, 1 H); 2.48 (m, 3 H); 2.66 (m, 3 H); 2.99 (m, 4H); 3.54 (d, J = 13 Hz, 1H); 3.62 (d, J = 13 Hz, 1H); 3.92 (m, 2H); 4.07 (m, 2H); 7.26 (m, 2H); 7.30 (m, 3 H).

To a mixture of compound 144 (0.688 g; 2.08 mmol) in methanol (10 ml) ammonium formate (0.432 g; 6.85 mmol) and Pd / C (0.022 g; 0.21 mmol). The reaction was heated to reflux for 1.5 hours, and then filtered through celite. The crude mixture was evaporated to give compound 145 as a oil that was used without further purification.

Yield: 95%

1 H NMR (CDCl 3): 1.73 (m, 1H); 2.25 (m, 2H); 2.55 (m, 1 H); 2.70 (m, 1 H); 2.85 (m, 1 H); 3.03 (m, 4H); 3.19 (m, 2H); 3.38 (m, 2 H); 3.87-4.07 (m, 3H); 4.24 (m, 1 HOUR).

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Examples 53.1-53.3

Following a procedure similar to that described in example 53, the compounds of table 53 were prepared.

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TABLE 53

248

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Example 54 2- (1,1-Dimethyl-2-oxo-2-pyrrolidin-1-ylethyl) -5- (3,5-dimethylphenyl) -4 - [(4-pyridin-4-ylpiperidin-1-yl) methyl] -6 H -thieno [2,3- b ] pyrrole

249

4-Piperidin-4-ylpyridine was added (see: Brown, George Robert; Newcombe, Nicholas John; Foubister, Alan John. "1- (Arylsulfonyl) -4 - [[4- (4-pyridyl) piperidin-1-yl ] carbonyllpiperazines and analogs useful as oxido-squalene cyclase inhibitors. "International application PCT (1998), WO 9835959 A1 19980820 CAN 129: 189345 AN 1998: 568822) (0.033 g, 0.20 mmol) to a solution of formaldehyde in acetic acid (2.8 ml formed from 0.61 ml of a 37% aqueous solution of formaldehyde in 100 ml of acetic acid, 0.21 mmol) and the mixture was stirred at room temperature for five minutes. A solution of 2- (1,1-dimethyl-2-oxo-2-pyrrolidin-1-ylethyl) -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b] was added dropwise ] pyrrole as a 1.1: 1 mixture with triethyl phosphite (0.083 g, 0.16 mmol) in acetic acid (1 ml) and the mixture was then allowed to stir at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue was partitioned between 2N hydrochloric acid and ethyl acetate. The aqueous layer was separated, made basic by the addition of 2N sodium hydroxide and extracted with ethyl acetate. The organic layer was separated, washed with a saturated brine solution, dried over magnesium sulfate and then evaporated to give a yellow oil. Flash chromatography on silica eluting with methanol (containing 7 N ammonia) in 2-3% dichloromethane gave the product as a pale yellow solid (0.043 g).

Yield: 50%

1 H NMR (CDCl 3): 1.6-1.76 (m, 12H + H2O), 1.78-1.86 (m, 2H), 2.10-2.18 (m, 2H), 2.36 (s, 6H), 2.46-2.55 (m, 1H), 3.08-3.20 (m, 4H), 3.50-3.58 (m, 2H), 3.60 (s, 2H), 6.84 (s, 1H), 6.95 (s, 1H), 7.14 (d, 2H), 7.28 (s, 2H), 8.45 (s, 1H), 8.50 (d, 2H).

EM-ESI: 541 [M + H] +

Intermediate 146 was prepared according with the following scheme:

250

2- (1,1-Dimethyl-2-oxo-2-pyrrolidin-1-ylethyl) -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole was prepared as follows:

5-Bromo-4-methylthiophene-2-carboxylic acid (Nemec, M .; Janda, Miroslav; Srogl, Jan; Stibor, I. Collection of Czechoslovak Chemical Communications (1974), 39 (12), 3527-31 was suspended .) (2.5 g, 11 mmol) in dichloromethane (25 ml) and dimethylformamide (0.1 ml). Oxalyl chloride (1.1 ml, 13 mmol) was added and the mixture was allowed to stir at room temperature for 2 hours. The solvent was evaporated and the crude acid chloride was dried in vacuo. The acid chloride was dissolved in a mixture of acetonitrile (20 ml), tetrahydrofuran (20 ml) and triethylamine (2.0 ml, 14 mmol) and the mixture was cooled in an ice bath. A solution of (trimethylsilyl) diazomethane (8.5 ml) in hexane (2.0 M, 17 mmol) was added dropwise and the mixture was allowed to stir in an ice bath for 20 hours. The solvent was evaporated and the residue was partitioned between 1 N hydrochloric acid and ethyl acetate. The organic layer was separated, dried over magnesium sulfate and then evaporated to leave a yellow solid. The crude alpha- diazoketone was dissolved in a mixture of benzyl alcohol (10 ml) and 2,4,6-trimethylpyridine (10 ml) and heated at 180 ° C for 2 hours. The mixture was allowed to cool and then purified directly by flash chromatography on silica eluting with a mixture of ethyl acetate in 10% iso- hexane to provide benzyl (5-bromo-4-methyl-2-thienyl) acetate ( 0.982 g) in the form of a dark yellow oil.

Yield: 27%

1 H NMR (CDCl 3): 2.12 (s, 3H), 3.74 (s, 2H), 5.15 (s, 2H), 6.61 (s, 1H), 7.32-7.37 (m, 5H). MS-ESI: 325/327 [M + H] +

A solution of (5-bromo-4-methyl-2-thienyl) acetate (0.982 g, 3.02 mmol) in tetrahydrofuran (3.5 ml) was added dropwise to a solution of di- iso -propilamiduro lithium [prepared from di- iso -propylamine (1.02 ml, 7.3 mmol) and a solution of n -butyllithium (4.54 ml) in hexane (1.6 M, 7.26 mmol ) in tetrahydrofuran (5 ml)] was cooled to -78 ° C. The mixture was stirred for 2 hours at -78 ° C and then methyl iodide (1.0 ml, 16 mmol) was added and the mixture was allowed to warm to room temperature over 4 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated and then washed with a 1 N solution of hydrochloric acid followed by a saturated brine solution. The ethyl acetate solution was dried over magnesium sulfate and then evaporated to leave benzyl 2- (5-bromo-4-methyl-2-thienyl) -2-methylpropanoate as a yellow oil that was used in the Next stage without further purification.

1 H NMR (CDCl 3): 1.61 (s, 6H), 2.11 (s, 3H), 5.12 (s, 2H), 6.59 (s, 1H), 7.25-7.37 (m, 5H).

A mixture of 2- (5-Bromo-4-methyl-2-thienyl) -2-methylpropanoate of benzyl and sodium hydroxide (0.33 g, 8.3 mmol) in methanol (10 ml) and water (2.5 ml) was heated at reflux for 1 hour. Solvent it was evaporated and the residue was triturated with 1 N hydrochloric acid and It was then extracted with ethyl acetate. The organic layer separated,  dried over magnesium sulfate and then evaporated to leave the acid 2- (5-Bromo-4-methyl-2-thienyl) -2-methylpropanoic acid  in the form of a yellow gum that was used in the next stage without purification.

1 H NMR (CDCl 3): 2.09 (s, 6H), 2.13 (s, 3H), 6.69 (s, 1H).

To a mixture of acid 2- (5-Bromo-4-methyl-2-thienyl) -2-methylpropanoic acid in dichloromethane (10 ml) with a catalytic amount of dimethylformamide oxalyl chloride (0.30 ml, 0.34 mmol) was added. The mixture was allowed to stir at room temperature for 2 hours. He Solvent was evaporated and the crude acid chloride was dried under vacuum. The crude acid chloride was dissolved in dichloromethane (10 ml) and was It cooled in an ice bath. Pyrrolidine (1.2 ml, 14 mmol) was added and the mixture was allowed to stir for 30 minutes while cooling In an ice bath. The mixture was poured into ethyl acetate (25 ml) and then extracted with 1 N hydrochloric acid. The layer Organic was washed with a saturated brine solution, dried over magnesium sulfate and then evaporated to leave the 1- [2- (5-Bromo-4-methyl-2-thienyl) -2-methylpropanoyl] pyrrolidine in the form of a red oil that was used in the next stage without purification.

EM-ESI: 316/318 [M + H] +

To a solution of 1- [2- (5-bromo-4-methyl-2-thienyl) -2-methylpropanoyl] pyrrolidine in acetic acid (8 ml) and water (5 ml) zinc powder (1, 0 g, 15 mmol). The mixture was heated at reflux for 24 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate and then washed sequentially with 1 N hydrochloric acid, 1 N sodium hydroxide and a saturated brine solution. The ethyl acetate solution was dried over magnesium sulfate and then evaporated. The residue was purified by flash chromatography on silica eluting with a mixture of ethyl acetate in 20-75% iso- hexane to provide 1- [2-methyl-2- (4-methyl-2-thienyl) propanoyl] pyrrolidine (0.151 g) in the form of a colorless solid.

Yield: 21% over 4 stages starting of the (5-Bromo-4-methyl-2-thienyl) acetate of benzyl.

1 H NMR (CDCl 3): 1.46 (s, 6H), 1.56-1.65 (m, 4H), 2.14 (s, 3H), 2.90 (width, 2H), 3.30 (width, 2H), 6.67 (d, 1H), 6.92-6.95 (m, 1 HOUR).

EM-ESI: 238 [M + H] +

Nitronium tetrafluoroborate (0.168 was added g, 1.26 mmol) to a solution of 1- [2-methyl-2- (4-methyl-2-thienyl) propanoyl] pyrrolidine  (0.145 g, 0.61 mmol) in dimethoxyethane (5 ml) cooled to -50 ° C. The mixture was allowed to warm to -30 ° C at 1 hour long The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated and washed sequentially with a saturated solution of sodium bicarbonate and then with a saturated brine solution. The solution of ethyl acetate was dried over magnesium sulfate and then evaporated to provide the 1- [2-methyl-2- (4-methyl-5-nitro-2-thienyl) propanoyl] pyrrolidine in the form of a yellow solid that was used in the next step without purification.

1 H NMR (CDCl 3): 1.62 (s, 6H), 1.73-1.81 (m, 4H), 2.58 (s, 3H), 3.03 (width, 2H), 3.53 (width, 2H), 6.66 (3, 1H).

A mixture of 1- [2-methyl-2- (4-methyl-5-nitro-2-thienyl) propanoyl] pyrrolidine and 3,5-dimethylbenzaldehyde (0.161 g, 1.2 mmol) in ethanol (5 ml) containing a catalytic amount of pyrrolidine was heated at reflux for 18 hours. The mixture was allowed to cool to room temperature and then the precipitate was filtered. The solid was washed with cold ethanol (2x5 ml) and then dried under vacuum to leave 1- (2- {4 - [( E ) -2- (3,5-dimethylphenyl) vinyl] -5-nitro-2 -thienyl} -2-methylpropanoyl-pyrrolidine (0.144 g) in the form of a bright yellow spongy solid that was used in the next step without further purification.

Yield: 59% over two stages at start from 1- [2-methyl-2- (4-methyl-2-thienyl) propanoyl] pyrrolidine

1 H NMR (d 6 DMSO): 1.57 (s, 6H), 1.64-1.70 (m, 4H), 2.30 (s, 6H), 3.04 (width, 2H), 3.37 (width, 2H), 7.02 (s, 1H), 7.25 (s, 2H), 7.61 (s, 1H), 7.63 (d, 1H), 7.88 (d, 1H).

A mixture of 1- (2- {4 - [( E ) -2- (3,5-dimethylphenyl) vinyl] -5-nitro-2-thienyl} -2-methylpropanoyl-pyrrolidine (0.134 g, 0.35 mmol ) and triethyl phosphite (1.0 ml) was heated at 180 ° C. for 1 hour.The mixture was concentrated and the residue was purified directly by flash chromatography on silica eluting with a mixture of ethyl acetate in 20% iso- hexane to provide the 2- (1,1-dimethyl-2-oxo-2-pyrrolidin-1-ylethyl) -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole (0.107 g) as of a red oil that was a 1.1: 1 mixture with triethyl phosphite.

Yield: 59% (based on a 1.1: 1 mixture with triethyl phosphite.

1 H NMR (CDCl 3): 1.65 (s, 6H), 1.70 (width, 4H), 2.34 (s, 6H), 3.13 (width, 2H), 3.54 (width, 2H), 6.57 (d, 1H), 6.74 (s, 1H), 6.87 (s, 1H), 7.19 (s, 2H), 9.25 (s, 1H).

EM-ESI: 367 [M + H] +

Therapeutic uses

The compounds of formula (I) are provided as medications to antagonize the activity of the hormone Gonadotropin-releasing (GnRH) in a patient, e.g. eg in Men and / or women. For this purpose, a compound of formula (I) is can provide as part of a pharmaceutical formulation that also includes a pharmaceutically acceptable diluent or carrier (e.g., water). The formulation can be in the form of tablets, capsules, granules, powders, syrups, emulsions (eg, emulsions of lipids), suppositories, ointments, creams, drops, suspensions (e.g. e.g., aqueous or oily suspensions) or solutions (e.g., aqueous or oily solutions). If desired, the formulation can include one or more selected additional substances regardless of stabilizing agents, wetting agents, emulsifying agents, buffers, lactose, sialic acid, stearate magnesium, terra alba, sucrose, corn starch, talc, jelly, agar, pectin, peanut oil, olive oil, butter cocoa and ethylene glycol.

The compound is preferably administered by orally to a patient, but other routes of administration, such as parental or rectal administration. For intravenous, subcutaneous or intramuscular administration, the patient can receive a daily dose of 0.1 mgkg -1 to 30 mgkg -1 (preferably 5 mgkg -1 to 20 mgkg -1) of the compound, administering the compound 1 to 4 times a day. The Intravenous, subcutaneous and intramuscular dose can be administered by bolus injection. Alternatively, the dose IV can be given by continuous infusion during a time frame. Alternatively, each patient can receive a daily oral dose that is approximately equivalent to the dose parenteral daily, administering the composition 1 to 4 times at day. A suitable pharmaceutical formulation is one suitable for the oral administration in unit dosage form, for example in the form of a tablet or capsule, which contains between 10 mg and 1 g (preferably, 100 mg and 1 g) of the compound of the invention.

Buffers, cosolvents can be used pharmaceutically acceptable (e.g., polyethylene glycol, propylene glycol, glycerol or EtOH) or complexing agents such how hydroxy-propyl-? -cyclodextrin, To help the formulation.

One aspect of the invention relates to the use of compounds according to the invention to reduce the secretion of LH and / or FSH by the pituitary gland of a patient. In this aspect, the reduction can be by reducing the biosynthesis of LH and FSH and / or a reduction in the release of LH and FSH by the pituitary gland. Therefore, the compounds of according to the invention can be used to treat and / or prevent therapeutically a condition related to sex hormones in a patient. By "prevent" is meant to reduce the risk of patient getting the condition. By "treat" is understood eradicate the condition or reduce its severity in the patient. The Examples of sex hormone related conditions are: a sex hormone dependent cancer, prostatic hypertrophy benign, myoma of the uterus, endometriosis, ovarian disease polycystic, uterine fibroids, prostate hypertrophy, myomas uterine, hirsutism and precocious puberty. The cancers examples Sex hormone dependent are: prostate cancer, cancer uterine, breast cancer and gonadotrophic pituitary adenoma.

The compounds of the invention can be used combined with other drugs and therapies used to treat / prevent Sex hormone related conditions.

If formulated as a fixed dose, said product combinations employ the compounds of this invention within the dosage range described herein memory, and the other pharmaceutically active agent within its approved dosage range. Sequential use is contemplated when a combination formulation is not suitable.

In the field of medical oncology, said combinations include combinations with the following categories of therapeutic agent:

i) anti-angiogenic agents (for example linomide, integrin function inhibitors αvβ3, angiostatin, endostatin, razoxin, thalidomide) and including endothelial vascular growth factors (VEGF) tyrosine kinase receptor (RTKI) inhibitors (for example the described in the publications of international applications of Patents No. WO-97/22596, WO-97/30035, WO-97/32856 and WO-98/13354, whose entire description of said documents are incorporated herein by reference);

ii) cytostatic agents such as anti-estrogens (for example tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrozole, vorazol, exemestane), anti-progestogens, anti-androgens (for example flutamide, nilutamide, bicalutamide, acetate cyproterone), testosterone inhibitors 5α-dihydroreductase (for example finasteride), anti-invasion agents (for example metalloprotease inhibitors such as marimastat and inhibitors of the function of the plasminogen activator receptor type urokinase) and growth factor function inhibitors (such growth factors include, for example the epidermal growth (EGF), growth factor derived from platelets and hepatocyte growth factors, said inhibitors include growth factor antibodies, growth factor receptor antibodies, inhibitors of tyrosine kinase and serine / threonine kinase inhibitors);

iii) biological response modifiers (for example interferon);

iv) antibodies (eg edrecolomab); Y

v) antiproliferative / antineoplastic drugs and their combinations, used in medical oncology, such as antimetabolites (for example antifolates such as methotrexate, fluoropyrimidines such as 5-fluorouracil, purine and adenosine analogs, cytosine arabinoside); antibiotics antitumor drugs (for example anthracyclines such as doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin, mitramycin); derivatives  of platinum (for example cisplatin, carboplatin); agents alkylating agents (eg nitrogen mustards, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); antimitotic agents (for example vinca alkaloids such as vincristine and taxoids such as taxol, taxotere); enzymes (for example asparaginase); thymidylate inhibitors synthase (for example raltitrexed); and topoisomerase inhibitors (for example, epipodophyllotoxins such as etoposide and teniposide, amsacrina, topotecan, irinotecan).

The compounds of the invention can also be use combined with surgery or radiotherapy.

essays

The ability of the compounds according to the invention to act as GnRH antagonists can be determined using the following in vitro assays .

Binding assay using pituitary GnRH receptor of rat

The test is carried out as follows:

1. The crude plasma membranes are incubated prepared from rat pituitary tissues in a Tris.HCl buffer (pH 7.5, 50 mM) containing serum albumin bovine (0.1%), [I-125] D-t-Bu-Ser6-Pro9-ethyl-amide-GnRH,  and the test compound. The incubation is at 4 ° C for 90 minutes 2 hours

2. Quickly filter and wash repeatedly through a fiberglass filter.

3. The radioactivity of the membrane bound radioligands using a gamma counter.

From this data, you can determine the IC 50 of the test compound as the concentration of compound necessary to inhibit radioligand binding to GnRH receptors in 50%. The compounds according to the present invention have activity at a concentration of 1 nM to 5 µM.

Binding assay using the human GnRH receptor

The raw membranes prepared from CHO cells expressing human GnRH receptors are sources of the GnRH receptor. The binding activity of the compounds according to the invention can be determined as an IC 50 which is the concentration of compound necessary to inhibit binding specific for [125 I] buserelin to GnRH receptors in 50% [125 I] buserelin (a GnRH analog peptide) is used here as a radiolabeled ligand of the receiver.

Assay to determine inhibition of LH release

The LH release assay can be used to demonstrate the antagonistic activity of the compounds, demonstrated by a reduction in the release of LH induced by GnRH.

Preparation of pituitary glands

Pituitary glands obtained from rats are Prepare as follows. Suitable rats are male Wistar rats (150-200 g) that have been kept at a temperature constant (e.g., 25 ° C) in a 12 hour light / 12 hour cycle darkness. Rats are sacrificed by decapitation before taking out aseptically pituitary glands to a tube containing Hank balanced salt solution (HBSS). After the glands are processed by:

1. Centrifugation at 250 x g for 5 minutes;

2. Aspiration of the HBSS solution;

3. Transfer of the glands to a plate petri before chopping on a scalpel;

4. Transfer of the chopped tissue to a tube centrifuge suspending the tissue three successive times in 10 ml of aliquots of HBSS containing 0.2% collagenase and 0.2% hyaluronidase;

5. Dispersion of the cells by gentle agitation of the tissue suspension while the tube is kept in a bath of water at 37 ° C;

6. Aspiration 20 to 30 times using a pipette, allowing the undigested pituitary fragments to deposit for 3 to 5 minutes;

7. Aspiration of suspended cells followed centrifugation at 1200 x g for 5 minutes;

8. Re-suspension of the cells in the middle DMEM culture containing 0.37% NaHCO3, serum 10% horse, 2.5% fetal bovine serum, no amino acids 1% essentials, 1% glutamine and 0.1% gentamicin;

9. Treatment of pituitary fragments undigested 3 times with 30 ml aliquots of collagenase and hyaluronidase;

10. Grouping of cell suspensions and dilution at a concentration of 3 x 10 5 cells / ml;

11. 1.0 ml of this suspension is placed in each one of a 24-well tray, keeping the cells in a humidified atmosphere of 5% CO2 / 95% air at 37 ° C for 3 to 4 days

Compound Test

The test compound is dissolved in DMSO at a final concentration of 0.5% in the incubation medium.

1.5 hours before the test, the cells are washed three times with DMEM containing 0.37% NaHCO3, serum 10% horse, 2.5% fetal bovine serum, no amino acids 1% essentials (100X), 1% glutamine (100X), 1% penicillin / streptomycin (10,000 units per ml) and 25 mM HEPES at pH 7.4. Immediately before the test, the cells they wash again twice in this medium.

After this, 1 ml of medium is added again contribution containing the test compound and 2 mM GnRH at two wells. For other test compounds (when it is desired to test more than one compound), these are added to other respective wells in duplicate Incubation is then carried out at 37 ° C for three hours.

After incubation, each well is analyzed separating the medium from the well and centrifuging the medium at 2000 x g for 15 minutes to separate any cellular material. Be Separate the supernatant liquid and the LH content is tested using a double antibody radioimmunological analysis. The comparison with a suitable control (no test compound) for determine if the test compound reduces the release of LH. The compounds according to the present invention have activity at a concentration of 1 nM to 5 µM.

Claims (15)

1. A compound of formula (I), 251 in the that: R1 is selected from: hydrogen or alkyl C 1-6 unsubstituted; R 2 is an optionally substituted monocyclic aromatic ring, in which the optional substituents in R 2 are independently selected from: C 1-6 alkyl, C 2-6 alkenyl, cyano, nitro, C 1-3 perfluoroalkyl, C 1-3 perfluoroalkoxy, aryl, aryl (C 1-6) alkyl, R 9 O (CH 2) p -, R ^ {9 C (O) O (CH 2) w -, R 9 OC (O) (CH 2) w -, R 16 S (O_ { n) (CH 2) w -, R 9 R 10 NC (O) (CH 2) w -,
R 9 R 10 N- or halogen; where w is an integer between 0 and 4, and R 9 and R 10 are as defined below; R 3 is selected from a group of Formula (IIa) to Formula (IIf): 252

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253

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254 R 4 is selected from: hydrogen or alkyl C 1-4; R 5 is a group of formula (III): 255 in which the group of formula (III) is selected from one of III-a to III-l, 256

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257

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258 at that: het represents a heterocyclic ring from 3 to 8 members, which contains 1 to 4 heteroatoms independently selected from O, N and S; R 23 and R 23a are selected regardless of hydrogen, fluoro or alkyl C 1-8; or R 23 and R 23a together with the carbon to which they are attached form a cycloalkyl ring of 3 to 7 members R 24 is selected from hydrogen, alkyl C 1-8, aryl, -R d -Ar, in the that R d represents C 1-8 alkylene and Ar represents aryl and heterocyclic ring of 3 to 8 members that optionally contains 1 to 3 additional heteroatoms independently selected from O, N and S; R 25 is selected from hydrogen; I rent C 1-8 and aryl; or when the group of formula (III) represents a group of formula III-a, III-b or III-i, then the NR 24 (- R 25) group represents a 3- to 8-membered heterocyclic ring containing optionally 1 to 3 additional heteroatoms independently selected from O, N and S; R 26 is selected from hydrogen or alkyl C 1-4; R 6 and R 6a are selected regardless of hydrogen, fluorine, alkyl C 1-6, aryl or aryl (C 1-6) alkyl, or R 6 and R 6a considered together and the carbon atom to which they are joined form a 3-7 carbocyclic ring members, or R 6 and R 6a considered together and the atom of carbon to which they are attached form a carbonyl group; or when A is not a direct link, the group

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259

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forms a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring that contains one or more heteroatoms; or the group

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260

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forms a heterocyclic ring that contains 3-7 carbon atoms and one or more heteroatoms; R 7 is selected from: hydrogen, alkyl C_ {1-6}, aryl (C 1-6) alkyl, aryl, heterocyclyl, heterocyclyl (C 1-6) alkyl. R 9 O-(C 1-6) alkyl -, R 9 R 10 N-(C 1-6) alkyl -, R 9 R 10 NC (O) -alkyl (C 1-6), -C (NR 9 R 10) = NH; or when R 3 is a group of formula (IIc) or (IId), R 7 is of formula -J-K-R 8; R 8 is selected from: (i) hydrogen, alkyl C 1-6, C 2-6 alkenyl, C 2-6 alkynyl, halogen-C 1-6 alkyl, (C 1-4) alkoxy-(C 1-4) alkyl,  hydroxy, hydroxyC 1-6 alkyl, cyano, N-(C 1-4) alkyl amino, N, N-di-(C 1-4) alkyl amino, (C 1-6) alkyl - S (O_n) -, -O-R b, -NR b R c, -C (O) -R b, -C (O) O-R b, -CONR b R c, NH-C (O) -Rb or -S (O_n) NRbRc, in which R b and R c are selected independently of hydrogen and C 1-4 alkyl optionally substituted with hydroxy, amino, N-(C 1-4) alkyl amino, N, N-di-(C 1-4) alkyl amino, HO-(C 2-4) alkyl - NH- or HO (C 2-4) alkyl - N (C 1-4) alkyl -; (ii) nitro when B is a group of formula (IV) and X is CH and p is 0; (iii) C 3-7 cycloalkyl, aryl or aryl (C 1-6) alkyl each one of which is optionally substituted with R 12, R 13 and R 14; (iv) - (Q) -aryl, - (Q) -heterocyclyl, -aryl- (Q) -aryl, each of which is optionally substituted with R 12, R 13 and R 14 in which - (Q) - is select from E, F or a direct link; (v) heterocyclyl or heterocyclyl (C 1-6) alkyl, each of which is optionally substituted with up to 4 substituents independently selected from R 12, R 13 and R 14; (vi) a group selected from R 12, R 13 and R 14; R 9 and R 10 are selected regardless of: hydrogen, hydroxy, alkyl C 1-6, aryl, aryl (C 1-6) alkyl, a 3-7 atom carbocyclic ring, heterocyclyl, heterocyclyl (C 1-6) alkyl, or R 9 and R 10 taken together can form a ring of 3-9 atoms, or R 9 and R 10 considered together with the carbon atom to which they are attached form a group carbonyl; R 11 is selected from: hydrogen, alkyl C 1-6, or N (R 9 R 10); R 12 is selected from: hydrogen, hydroxy, R 17 R 18 N (CH 2) cc -, R 17 R 18 C (O) (CH 2) cc -, (C 1-6) alkyl - C (O) N (R 9) (CH 2) cc -, (C 1-6) alkyl - SO 2 N (R 9) -,  aryl-SO 2 N (R 9) -, perfluoroalkyl (C 1-3) - SO 2 N (R 9) -; (C 1-6) alkyl - N (R 9) SO 2 -,  aryl-N (R 9) SO 2 -, perfluoroalkyl (C 1-3) - N (R 9) SO 2 -alkanoyl (C 1-6) - N (R 9) SO 2 -; aryl-C (O) N (R 9) SO 2 -, (C 1-6) alkyl - S (O_n) -, aryl-S (O n) -, perfluoroalkyl C 1-3, perfluoroalkoxy C 1-3, C 1-6 alkoxy, carboxy, halogen, nitro or cyano; R 13 and R 14 are selected Regardless of: hydrogen, hydroxy, oxo, alkyl C 1-6, C 1-6 alkanoyl, C 2-6 alkenyl, cyano, nitro, perfluoroalkyl C 1-3, perfluoroalkoxy C_ {1-3}, aryl, aryl (C 1-6) alkyl, R 9 O (CH 2) s -, R 9 (O) O (CH 2) s -, R 9 OC (O) (CH 2) s -, R 16 S (O n) (CH 2) s -, R 9 R 10 NC (O) (CH 2) s - or halogen; R 15 is selected from: hydrogen, alkyl C 1-6, R 19 OC (O) -, R 9 R 10 NC (O) -, R 9 C (O) -, R 9 S (O n) -; R 16 is selected from: hydrogen, alkyl C 1-6, perfluoroalkyl C 1-3 or aryl; R 17 is independently selected from: hydrogen, hydroxy, cyano or C 1-6 alkyl; R 18 is a group of formula R 18a -C (R 9 R 10) 0-1 - wherein R 18a is selected from: R 19 OC (O) -, R 9 R 10 NC (O) -, R 9 R 10 N-, R 9 C (O) -, R 9 C (O) N (R 10) -, R 9 R 10 NC (O) -, R 9 R 10 NC (O) N (R 10) -, R 9 SO 2 N (R 10) -, R 9 R 10 NSO 2 N (R 10) -, R 9 C (O) O-, R 9 OC (O) -, R 9 R 10 NC (O) O-, R 9 O-, R 9 S (O n) -, R 9 R 10 NS (O n) -, hydrogen, C 1-6 alkyl, heterocyclyl; or R 17 and R 18 when considered together they form a carbocyclic ring of 3-7 atoms or  optionally substituted heterocyclyl; R 19 is selected from: hydrogen, alkyl C 1-6, aryl, aryl (C 1-6) alkyl, C 3-7 cycloalkyl, heterocyclyl or heterocyclyl (C 1-6) alkyl; R 20 is selected from R 12 or R 13; R 21 and R 22 are independently selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted heterocyclyl, heterocyclyl (C 1-6 alkyl) }) optionally substituted, optionally substituted C 3-6 alkenyl, optionally substituted C 3-6 alkynyl, - (C 1-5 alkyl) aa -S (O n) - (alkyl
C 1-5) bb -; R 9 R 10 N-alkyl (C 2-6), R 9 O-alkyl (C 2-6) or R 9 R 10 NC (O) -C 2-6 alkyl, with the proviso that R 9 and R 10 independently or considered together are not optionally substituted aryl or aryl (C 1-6) alkyl ) optionally substituted; or R 21 and R 22 considered together form an optionally substituted non-aromatic heterocyclic ring; wherein the optional substituents of R 21 and R 22 are independently selected from C 1-8 alkyl, C 3-8 cycloalkoxy, C 1-6 alkoxy, halogen, Hal_ { 3} C-, Hal 2 CH-, HalCH 2 -, Hal 3 CO-, Hal 2 CHO or Hal CH 2 O, in which Hal represents halogen, R g CH 2 O-, R h C (O) N (R) -, R h SO 2 N (R) - or R g -R h N- , in which R g and R h independently represent hydrogen or C 1-8 alkyl, or R g -R h N- represents an optionally substituted C 3 heterocyclic ring -8, preferably C 3-6, which optionally contains from 1 to 3 additional heteroatoms independently selected from O, N and S, hydrogen, or R k C (O) O- or R k C (O) -, R k represents hydrogen, optionally substituted phenyl or alkyl
C 1-6; for optional ring replacement heterocyclic represented by R g -R b N-, at least one substituent can be independently selected from alkyl C 1-6, phenyl, CF 3 O-, F 2 CHO-, alkoxy C_ {1-8}, (C 1-8) alkoxy-C (O), phenoxycarbonyl, phenoxy, C 1-8 alkanoyl, carboxy; (C 1-8) alkyl - S (O_ {nn})  where nn is an integer between 0 and 2, hydroxy; halogen, R m R n N- in which R m and R n are independently hydrogen or C 1-6 alkyl, and nitro

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A is selected from: (i) a direct link; (ii) C 1-5 alkylene optionally substituted in which the optional substituents are independently selected from: alkyl C 1-6, aryl or aryl (C 1-6) alkyl; (iii) a carbocyclic ring of 3-7 atoms; (iv) a carbonyl group or -C (O) -C (R d R d) -, wherein R d is independently selected from hydrogen and C 1-2 alkyl;

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or when R 3 is a group of formula (IIa) or (IIb), the group 261 forms a heterocyclic ring that contains 3-7 carbon atoms and one or more heteroatoms; or when R 3 is a group of formula (IIa), (IIb), (IIc) or (IId), the group 262 forms a heterocyclic ring that contains 3-7 carbon atoms and one or more heteroatoms;

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B is selected from: (i) a direct link; (ii) a group of formula (IV) 263 at that: X is selected from N, CH or a ring saturated heterocyclic, in which in position (a) the formula (IV) is attached to the nitrogen atom and the group (CH2) p is bound to R 8; Y (iii) an independently selected group of: C 1-6 alkylene, cycloalkyl C 3-7, C 3-6 alkenylene, C 3-6 alkynyl, alkoxy C 1-6, (alkyl C 1-5 (a) -S (O n) - (alkyl C_ 1-5) bb -, (alkyl C 1-5) aa -O- (alkyl C_ 1-5) bb - or (alkyl C 1-5) aa -N (R 15) - (alkyl  C_ 1-5) bb, in which R 15 and the chain (C 1-5 alkyl) aa or (alkyl C_ 1-5) bb can be joined to form a ring; or the group -B-R 8 represents a group of formula (V) 264 or the group 265 together it forms a heterocyclic ring optionally substituted containing 4-7 atoms of carbon; or the group 266

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forms a heterocyclic ring that contains 3-7 carbon atoms and one or more heteroatoms; E is -O-, -S (O_ {n}), -C (O) -, -NR 15 - or -C (R 9 R 10) q; F is -E (CH 2) r - or - (CH 2) r E-; G is selected from: hydrogen, halogen, CN, NO_ {2}, N, O, S (O_ {n}), C (O), C (R 9 R 10) t, alkenylene C 2-6, C 2-6 alkynylene, heterocyclyl or a direct link to R18, J is a group of formula: - (CH 2) s -L- (CH 2) s - in which when s is greater than 0, the alkylene group is optionally substituted, in which the optional substituents are independently select from alkyl C 1-8, C 3-8 cycloalkoxy, C 1-6 alkoxy, halogen, R g CH 2 O-, R h C (O) N (R) -, R h SO 2 N (R) - or R g -R h N-, in which R g and R h represent independently hydrogen or C 1-8 alkyl, or R g -R h N- represents a ring C 3-8 heterocyclic optionally containing 1 to 3 additional heteroatoms independently selected of O, N and S, hydrogen, or R k C (O) O- or R k C (O) -, and R k represents hydrogen, phenyl or alkyl C_ {1-6}, or the group 267

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together it forms a heterocyclic ring which contains 4-7 atoms of carbon; K is selected from: a direct link, - (CH2) s1 -, - (CH2) s2 -O- (CH2) s -, - ( CH 2) s1 C (O) - (CH 2) s 2 -, - (CH 2) s 1 -S (O n) -
(CH2) s2 -, - (CH2) s1 -N (R18) - (CH2) s2 -, - (CH2 ) s1 -C (O) N (R9) - (CH2) s2 -, - (CH2) s1 -N (R9 }) C (O) - (CH2) s2 -, - (CH2) s1 -N (R9) C (O) N (R9 ) - (CH 2) s 2 -, - (CH 2) s 1 -OC (O) - (CH 2) s 2 -, - (CH 2) s1 -C (O) O- (CH2) s2 -, - (CH2) s1 -N (R9 C (O) O- (CH_ {2} s2, - (CH2) s1 -OS (O_n) - (- (CH2n - - - (CH2) s1 - S (O_n) - O- (CH2) s2, - (CH2) s1 -S (O) 2 N (R9) - (CH 2) s 2 -, or - (CH 2) s 1 -N (R 9 S (O) 2 (CH 2) s2 -, wherein the groups - (CH 2) s 1 - and - (CH 2) s 2 - are independently optionally substituted with hydroxy or C 1-4 alkyl; L is selected from aryl or heterocyclyl; m is an integer from 0 to 4; n is an integer from 0 to 2; p is an integer from 0 to 4; q is an integer from 0 to 4; r is an integer from 0 to 4; s is an integer from 0 to 4; s1 and s2 are independently selected from a integer from 0 to 4, and s1 + s2 is less than or equal to 4; Y t is an integer from 0 to 4; aa and bb are independently selected from 0 or one; cc is an integer from 0 to 2; with the condition of (i) when G is hydrogen, halogen, CN or NO 2, then R 17 and R 18 are both absent; (ii) when G is O, S (O_ {n}), C (O) or C (R 11 R 12) t then G is substituted with a single independently selected group of the definition of R 17 or R 18, and when G is a bond direct to R 18 then G is substituted with a single group selected from R18; Y (iii) when R3 is a group of formula (IIb), B is a group of formula (TV), R 8 is selected from group (i) or (ii) above, R 11 is a group of formula N (R 10 R 11) and R 1, R 2 and R 5 are as defined above, then R 4 cannot be hydrogen; or one of its salts, hydrolysable esters in vivo or solvates. 2. A compound according to claim 1, in the that R1 is hydrogen. 3. A compound according to claim 1 or claim 2, wherein R3 is selected from a group of formula (IIa) or formula (IIb). 4. A compound according to claim 3, in the that B is C 1-6 alkylene or the group

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268

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form a heterocyclic ring C_ {5-7}. 5. A compound according to claim 1 or claim 2, wherein R3 is selected from a group of formula (IIc) or formula (IId). 6. A compound according to claim 5, in the that the group

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269

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together it forms a heterocyclic ring optionally substituted containing 4-7 atoms of carbon. 7. A compound according to claim 6, wherein K is selected from: - (CH2) s -, - (CH2) s -O- (CH2) s -, - (CH 2) s -
C (O) - (CH 2) s -, - (CH 2) s -N (R 18) - (CH 2) s -, - (CH 2) s -C (O) N (R 18) - (CH 2) s -, - (CH 2) s -N (R 18) C (O) - (CH 2) s -, - (CH 2) s -S (O) 2 N (R 18 ) - (CH 2) s -, or - (CH 2) s -NHS (O) 2 - (CH 2) s -. 8. A compound according to any one of the claims 3, 4, 5, 6 or 7, wherein R 8 is selected from (i) hydrogen, alkyl C 1-6, C 2-6 alkenyl, halogen-C 1-6 alkyl, hydroxy, cyano, (C 1-6) alkyl - S (O_n) -,  -O-R b, (C 1-4) alkoxy-(C 1-4) alkyl, -C (O) -R b, C (O) O-R b, -NH-C (O) -R b, N, N-di-(C 1-4) alkyl amino,  -S (O_n) NR b R c in which R b and R c are selected independently of hydrogen and C 1-6 alkyl, and n is 0, 1 or 2; (ii) - (Q) -aryl; (iii) C 4-7 heterocyclyl, or (iv) C 3-7 carbocyclyl.

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9. A compound according to any one of the preceding claims, wherein the group of formula (III) is selected from one of III-a, III-g, III-h, or III-l; 270 at that: R 23, R 23a, R 24 and R 25 are as defined above. 10. A compound according to any one of the preceding claims, wherein R2 is selected from an optionally monocyclic aromatic ring structure substituted in which the optional substituents are selected from cyano, NR e R f, C 1-6 alkyl, alkoxy C 1-8 or halogen, in which R e and R f are independently selected from hydrogen, alkyl C 1-6 or aryl. 11. A compound selected from: 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [1-oxa-2-methyl-2- {4- ( 1,1-dioxidotetrahydro-3-thienyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole; 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (pyrrolidin-1-ylcarbonylmethyl) piperazin- 1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole; 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- {4- (2,4-dioxo-1, 2,3,4-tetrahydropyrimidin-b-ylmethyl) piperazin-1-yl} ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole; 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {3-hydroxypyrrolidin-1-ylcarbonyl} piperidin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole; 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {3-oxo-3-pyrrolidin- 1-ilprop-2-yl} piperazin-1-yl) ethyl] -5- (3,5-dimethylphenyl) -6H-thieno [2,3-b] pyrrole;  Y 2- [1,1-Dimethyl-2-oxo-2- (7-azabicyclo [2.2.1] heptan-7-yl) ethyl] -4- [2- (4- {morpholinocarbonyl} piperidin-1-yl) ethyl-5- (3,5-dimethylphenyl) -6 H -thieno [2,3- b ] pyrrole; or one of its salts, hydrolysable esters in vivo or solvates. 12. A compound, or its salt, hydrolysable ester in vivo or solvate, according to any one of claims 1 to 11 for use as a medicament. 13. A pharmaceutical formulation comprising compound, or its salt, hydrolysable ester in vivo or solvate, according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or diluent. 14. Use of a compound, or its salt, hydrolysable ester in vivo or solvate, according to any one of claims 1 to 11, in the manufacture of a medicament for administration to a patient, to treat and / or therapeutically prevent a related condition with sex hormones in the patient. 15. A process for producing a compound, or its salt, hydrolysable ester in vivo or solvate, according to any one of claims 1 to 11, wherein the process comprises a reaction step selected from any one of (a) to ( i): (a) Reaction of a compound of formula XXXII with a compound of formula H-R 5 'to form a compound of formula (I), 271 in which X1 is selected from: 272 L1 is a movable group; Y H-R 5 'is selected from: 273 (b) Reaction of a compound of formula XXXIII with a compound of formula L 2 -R 5 '' to form a compound of formula (I), 274 in which X2 is selected from: 275 R 7a is selected from the above definition of R 7 or R 22, and L 2 -R 5 '' is selected from: L 2 -B-R 8, L 2 -J-K-R 8 and L 2 -R 21, (c) For compounds of formula (I) in which R 3 is a group of formula (IIa), (IIb), (IIc) or (IId) and R 7 is different from a part of a heterocyclic ring or hydrogen, reaction of a compound of formula (I) in which R 3 is a group of formula (IIa), (IIb), (IIc) or (IId) and R 7 is hydrogen with a group of formula L 3 -R 7a, in which R 7a is as has been defined above for R 7 with the exclusion of hydrogen and L3 is a group scrollable; (d) For the compounds of formula (I) in which R 3 is a group of formula (IIe) or (IIf) and R 21 is different of hydrogen, reaction of a compound of formula (I) in which R 3 is a group of formula (IIe) or (IIf) and R 21 is hydrogen with a group of formula L 4 -R 21a, where R 21a is as defined above for R 21 with the exclusion of hydrogen and L 4 is a group scrollable; (e) For the compounds of formula (I) in which R 3 is a group of formula (IIe) or (IIf) and R 22 is different of hydrogen, reaction of a compound of formula (I) in which R 3 is a group of formula (IIe) or (IIf) and R 22 is hydrogen with a group of formula L 5 -R 22a, wherein R 22a is as defined above for R 22 with the exclusion of hydrogen and L 5 is a group scrollable;

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(f) For the compounds of formula (I) in which R 3 is a group of formula (IIc) or (IId) and the group

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276

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together it forms a heterocyclic ring optionally substituted containing 4-7 atoms of carbon, reaction of a compound of formula XXXIVa or XXXIVb, with a compound of formula L 6 -K-R 8, in which L 6 is a group scrollable

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277

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(g) For compounds of formula (I) wherein R 3 is a group of formula (IIc) or (IId), reaction of a compound of formula XXXVa or XXXVb, with a compound of formula L 7 -K '' - R 8, in which L7 is a movable group, and in which groups K 'and K' 'comprise groups that when they react together form K,

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278

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(h) reaction of a compound of formula XXXVI with an electrophilic compound of formula L 8 -R 5, in which L 8 is a group scrollable

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279

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(i) reaction of a compound of formula XXXVII with a compound of formula L 8 -R 5, in which L 8 is a group scrollable

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280

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and later, if it is necessary: i) conversion of a compound of formula (I) into another compound of formula (I); ii) elimination of any group protective; iii) formation of a salt, hydrolysable ester in vivo or solvate.